NCT01602315

A Phase Ib/II Study of BYL719 and Cetuximab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Terminated Phase 1, PHASE2 Results posted Last updated 29 December 2020

What this trial tests

Phase 1, PHASE2 trial testing BYL719 as film-coated (FC) whole tablets in Recurrent Head and Neck Squamous Cell Carcinoma in 179 participants. Terminated before completion.

Timeline

12 November 2012

Primary endpoint
16 September 2016

16 September 2016

Quick facts

Lead sponsor	Novartis Pharmaceuticals
Phase	Phase 1, PHASE2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	179
Start date	12 November 2012
Primary completion	16 September 2016
Estimated completion	16 September 2016
Sites	29 locations across France, Hong Kong, Netherlands, Taiwan, South Korea, Canada, Australia, Singapore

Drugs / interventions tested

• BYL719 as film-coated (FC) whole tablets — full drug profile →
• BYL719 as dispersible tablets (DT) — full drug profile →
• cetuximab (cetuximab) — full drug profile →
• BYL719 drink suspension — full drug profile →

Conditions studied

• Recurrent Head and Neck Squamous Cell Carcinoma — all drugs for Recurrent Head and Neck Squamous Cell Carcinoma →
• Metastatic Head and Neck Squamous Cell Carcinoma — all drugs for Metastatic Head and Neck Squamous Cell Carcinoma →

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

18 and older, any sex, with Recurrent Head and Neck Squamous Cell Carcinoma or Metastatic Head and Neck Squamous Cell Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Phase Ib Arms A: Probability That Dose Limiting Toxicities (DLTs) Rate is in the Recommended Phase 2 Dose in Cycle 1 (Cycle 1=28 Days) Primary · until disease progression or intolerable toxicity (approximately 6 months)

Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in arm A (BYL719 administered as a whole tablet in patients able to swallow the tablets). Dose recommendation was based on posterior summaries including the mean, median, standard deviation, 95%-credibility interval, and the probability that the true DLT rate for each dose combination lies in one of the following categories: (0%, 16%) under-dosing; (16%, 35%) targeted toxicity; (35%, 100%) exce

Posterior probabilities that Pr(DLT) in 0-0.16

Group	Value	95% CI
Arm A - 300mg BYL719+Cetuximab	0.764
Arm A - 400mg BYL719+Cetuximab	0.086

Posterior probabilities that Pr (DLT) in 0.16-0.35

Group	Value	95% CI
Arm A - 300mg BYL719+Cetuximab	0.222
Arm A - 400mg BYL719+Cetuximab	0.376

Posterior probabilities that Pr (DLT) in 0.35-1

Group	Value	95% CI
Arm A - 300mg BYL719+Cetuximab	0.015
Arm A - 400mg BYL719+Cetuximab	0.538

Phase Ib Arm B: Probability That Distribution of Dose Limiting Toxicities (DLTs) is in the Recommended Phase 2 Dose in Cycle 1 (Cycle 1=28 Days) Primary · until disease progression or intolerable toxicity (approximately 6 months)

Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in arm B (crushed film-coated tablets as an oral suspension with swallowing dysfunction). Dose recommendation was based on posterior summaries including the mean, median, standard deviation, 95%-credibility interval, and the probability that the true DLT rate for each dose combination lies in one of the following categories: (0%, 16%) under-dosing; (16%, 35%) targeted toxicity; (35%, 100%) exce

Posterior probabilities that Pr(DLT) in 0-0.16

Group	Value	95% CI
Arm B- 300mg BYL719+Cetuximab	0.267

Posterior probabilities that Pr (DLT) in 0.16-0.35

Group	Value	95% CI
Arm B- 300mg BYL719+Cetuximab	0.664

Posterior probabilities that Pr (DLT) in 0.35-1

Group	Value	95% CI
Arm B- 300mg BYL719+Cetuximab	0.069

For Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 Days) Primary · until disease progression or intolerable toxicity (approximately 6 months)

Estimation of Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in arm A (BYL719 administered as a whole tablet in patients able to swallow the tablets) and arm B (BYL719 administered as a drinkable suspension in patients with swallowing dysfunction). 6 months is an approximate timeframe.

Group	Value	95% CI
Arm A - 300mg BYL719+Cetuximab	1
Arm A - 400mg BYL719+Cetuximab	2
Arm B - BYL719 + Cetuximab, Oral Suspension	4
Arm C - BYL719+Cetuximab, Dispersible Tablets	2
All Patients	9

Phase II Arms 1 and 2: Progression Free Survival (PFS) as Per RECIST v1.1 by Central Radiology Review Primary · approximately 6 months

Assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab. 6 months is an approximate timeframe.

Number of PFS events

Group	Value	95% CI
BYL719+ Cetuximab (Randomized)	46	0.643 – 1.529
Monotherapy Cetuximab (Randomized)	27

Progression

Group	Value	95% CI
BYL719+ Cetuximab (Randomized)	33
Monotherapy Cetuximab (Randomized)	25

Number of censored

Group	Value	95% CI
BYL719+ Cetuximab (Randomized)	25
Monotherapy Cetuximab (Randomized)	8

Death

Group	Value	95% CI
BYL719+ Cetuximab (Randomized)	13
Monotherapy Cetuximab (Randomized)	2

Phase II Arm 3: Progression Free Survival (PFS) as Per RECIST V1.1 Primary · approximately 6 months

Assessment of the anti-tumor activity of BYL719 in combination with cetuximab in patients resistant to platinum-based therapy and cetuximab.

Group	Value	95% CI
BYL719+ Cetuximab (Non-randomized)	3.896	2.868 – 5.241

Phase Ib: Area Under Curve (AUC) 0-24 for BYL719 by Treatment Primary · 6 months

Comparison of single-dose exposure of BYL719 dispersible tablet via G-tube in combination with cetuximab in RM HNSCC to that of Arm A (film-coated tables)

AUCinf

Group	Value	95% CI
Arm A - 300mg BYL719+Cetuximab	22600	16600 – 48500
Arm C: BYL719+Cetixumab, Dispersible Tablets	24100	9290 – 33200
Arm A: 400mg BYL719 + Cetuximab	27800	17200 – 60100
Arm B: 300mg BYL719 + Cetuximab	27300	15700 – 47400

AUC0_24

Group	Value	95% CI
Arm A - 300mg BYL719+Cetuximab	18800	5590 – 43400
Arm C: BYL719+Cetixumab, Dispersible Tablets	19400	7580 – 32100
Arm A: 400mg BYL719 + Cetuximab	26300	16000 – 56100
Arm B: 300mg BYL719 + Cetuximab	25600	14600 – 42100

AUClast

Group	Value	95% CI
Arm A - 300mg BYL719+Cetuximab	19200	5830 – 42700
Arm C: BYL719+Cetixumab, Dispersible Tablets	22100	4390 – 31800
Arm A: 400mg BYL719 + Cetuximab	26200	15800 – 55600
Arm B: 300mg BYL719 + Cetuximab	25000	14400 – 41900

Phase II: Progression Free Survival (PFS) as Per RECIST v 1.1 Secondary · approximately 6 months

Phase II, Scheme 1 (Arm 2B): To further assess the anti-tumor activity of BYL719 + cetuximab in the setting of resistance to single agent cetuximab

Number of PFS

Group	Value	95% CI
Arm 2B - BYL719+Cetuximab	12

Progression

Group	Value	95% CI
Arm 2B - BYL719+Cetuximab	9

Death

Group	Value	95% CI
Arm 2B - BYL719+Cetuximab	3

Number of Censored

Group	Value	95% CI
Arm 2B - BYL719+Cetuximab	4

Phase Ib: Progression Free Survival (PFS) as Per RECIST v1.1 Secondary · approximately 6 months

Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A, B and C.

PFS event (Progression)

Group	Value	95% CI
Arm A - 300mg BYL719+Cetuximab	5
Arm A - 400mg BYL719+Cetuximab	2
Arm B - BYL719 + Cetuximab, Oral Suspension	10
Arm C - BYL719+Cetuximab, Dispersible Tablets	2

PFS event (Death)

Group	Value	95% CI
Arm A - 300mg BYL719+Cetuximab	2
Arm A - 400mg BYL719+Cetuximab	2
Arm B - BYL719 + Cetuximab, Oral Suspension	1
Arm C - BYL719+Cetuximab, Dispersible Tablets	1

Number of Censored

Group	Value	95% CI
Arm A - 300mg BYL719+Cetuximab	9
Arm A - 400mg BYL719+Cetuximab	1
Arm B - BYL719 + Cetuximab, Oral Suspension	7
Arm C - BYL719+Cetuximab, Dispersible Tablets	3

Phase II: Randomized Best Overall Response as Per RECIST v1.1 Secondary · approximately 6 months

Scheme 1 (Arms 1 and 2): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab

Complete Response

Group	Value	95% CI
Arm 1 - BYL719+Cetuximab (Randomized)	1
Arm 2 - Monotherapy Cetuximab (Randomized)	0
All Patients	1

Partial Response

Group	Value	95% CI
Arm 1 - BYL719+Cetuximab (Randomized)	6
Arm 2 - Monotherapy Cetuximab (Randomized)	2
All Patients	8

Stable Disease

Group	Value	95% CI
Arm 1 - BYL719+Cetuximab (Randomized)	24
Arm 2 - Monotherapy Cetuximab (Randomized)	8
All Patients	32

Progressive Disease

Group	Value	95% CI
Arm 1 - BYL719+Cetuximab (Randomized)	17
Arm 2 - Monotherapy Cetuximab (Randomized)	12
All Patients	29

Non-CR/Non-PD (NCRNPD)

Group	Value	95% CI
Arm 1 - BYL719+Cetuximab (Randomized)	6
Arm 2 - Monotherapy Cetuximab (Randomized)	10
All Patients	16

Unknown

Group	Value	95% CI
Arm 1 - BYL719+Cetuximab (Randomized)	17
Arm 2 - Monotherapy Cetuximab (Randomized)	3
All Patients	20

Phase II: Non-Randomized Best Overall Response as Per RECIST v1.1 Secondary · approximately 6 months

Scheme 1 (Arm 3): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab

Complete Response (CR)

Group	Value	95% CI
Arm 3 - BYL719+Cetuximab	1

Partial Response (PR)

Group	Value	95% CI
Arm 3 - BYL719+Cetuximab	2

Stable Disease (SD)

Group	Value	95% CI
Arm 3 - BYL719+Cetuximab	8

Progressive Disease (PD)

Group	Value	95% CI
Arm 3 - BYL719+Cetuximab	5

Non-CR/Non-PD (NCRNPD)

Group	Value	95% CI
Arm 3 - BYL719+Cetuximab	6

Unknown

Group	Value	95% CI
Arm 3 - BYL719+Cetuximab	7

Phase II: Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1 Secondary · approximately 6 months

Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arms 1 and 2.

Overall response rate (ORR) (CR or PR)

Group	Value	95% CI
Arm 1 - BYL719+Cetuximab (Randomized)	9.9	4.1 – 19.3
Arm 2 - Monotherapy Cetuximab (Randomized)	5.7	0.7 – 19.2
All Patients (Phase II)	8.5	4.0 – 15.5

Disease control rate 1 (DCR 1) (CR or PR or SD)

Group	Value	95% CI
Arm 1 - BYL719+Cetuximab (Randomized)	43.7	31.9 – 56.0
Arm 2 - Monotherapy Cetuximab (Randomized)	28.6	14.6 – 46.3
All Patients (Phase II)	38.7	29.4 – 48.6

DCR 2 (CR or PR or SD or Non-CR/Non-PD)

Group	Value	95% CI
Arm 1 - BYL719+Cetuximab (Randomized)	52.1	39.9 – 64.1
Arm 2 - Monotherapy Cetuximab (Randomized)	57.1	39.4 – 73.7
All Patients (Phase II)	53.8	43.8 – 63.5

Phase II: Non-Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1 Secondary · approximately 6 months

Scheme 1 (arm 3): Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm 3 (non-randomized arm)

Overall response rate (ORR) (CR or PR)

Group	Value	95% CI
Arm 3 - BYL719+Cetuximab	10.3	2.2 – 27.4

Disease control rate 1 (DCR 1) (CR or PR or SD)

Group	Value	95% CI
Arm 3 - BYL719+Cetuximab	37.9	20.7 – 57.7

DCR 2 (CR or PR or SD or Non-CR/Non-PD)

Group	Value	95% CI
Arm 3 - BYL719+Cetuximab	58.6	38.9 – 76.5

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Treatment until Last Patient Last Visit.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Arm A - 300mg BYL719+Cetuximab

Serious: 9/15 (60%)

Deaths: —

Arm A: 400 mg BYL719 + Cetuximab

Serious: 4/5 (80%)

Deaths: —

Arm B - BYL719 + Cetuximab Oral Suspension

Serious: 12/18 (67%)

Deaths: —

Arm C - BYL719+Cetuximab Dispersible Tablets

Serious: 4/6 (67%)

Deaths: —

Arm 1 - BYL719+Cetuximab (Randomized)

Serious: 40/69 (58%)

Deaths: —

Arm 2 - Monotherapy Cetuximab (Randomized)

Serious: 15/35 (43%)

Deaths: —

Arm 3 - BYL719+Cetuximab (Non-randomized)

Serious: 15/29 (52%)

Deaths: —

All Patients

Serious: 99/178 (56%)

Deaths: —

Serious adverse events (102 terms)

Reaction	System	Arm A - 300mg BYL719+Cetux…	Arm A: 400 mg BYL719 + Cet…	Arm B - BYL719 + Cetuximab…	Arm C - BYL719+Cetuximab D…	Arm 1 - BYL719+Cetuximab (…	Arm 2 - Monotherapy Cetuxi…	Arm 3 - BYL719+Cetuximab (…	All Patients
Pneumonia	Infections and infestations	—	—	—	—	—	—	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Tumour haemorrhage	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—	—
Muscular weakness	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—
General physical health deterioration	General disorders	—	—	—	—	—	—	—	—
Cellulitis	Infections and infestations	—	—	—	—	—	—	—	—
Wound infection	Infections and infestations	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Aspiration	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Respiratory distress	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Mouth haemorrhage	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Pain	General disorders	—	—	—	—	—	—	—	—
Drug hypersensitivity	Immune system disorders	—	—	—	—	—	—	—	—
Lung infection	Infections and infestations	—	—	—	—	—	—	—	—

Other adverse events (227 terms — click to expand)

Reaction	System	Arm A - 300mg BYL719+Cetux…	Arm A: 400 mg BYL719 + Cet…	Arm B - BYL719 + Cetuximab…	Arm C - BYL719+Cetuximab D…	Arm 1 - BYL719+Cetuximab (…	Arm 2 - Monotherapy Cetuxi…	Arm 3 - BYL719+Cetuximab (…	All Patients
Hyperglycaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Dermatitis acneiform	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Paronychia	Infections and infestations	—	—	—	—	—	—	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Skin fissures	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—
Hypophosphataemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—	—	—
Hypoalbuminaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Folliculitis	Infections and infestations	—	—	—	—	—	—	—	—
Hypercalcaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Dysphonia	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—	—	—	—	—	—

Most-reported serious reactions: Pneumonia, Hyperglycaemia, Pyrexia, Sepsis, Dyspnoea, Dysphagia, Tumour haemorrhage, Muscular weakness.

Data from ClinicalTrials.gov NCT01602315 adverse events section.

Sponsor's own description

This was a multi-center, open-label, Phase Ib dose escalation /Phase II study in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) patients considered to be resistant, ineligible or intolerant to platinum-based chemotherapy. The Phase Ib included three arms. Three different methods of administration and two different BYL719 formulations were studied to determine the MTD and/or RP2D of BYL719 in combination with cetuximab:

Arm A - film-coated whole tablets were orally administered to patients who were able to swallow the tablets; Arm B - a drinkable suspension prepared from crushed film-coated tablets was administered orally to patients with swallowing dysfunction Arm C - a suspension from a dispersible tablet administered via G-tube, in patients with swallowing dysfunction. Arm C was used to investigate the pharmacokinetics (PK), compared to Arm A (film coated tablet), and safety of the dispersible tablet of the dispersible tablet formulation of BYL719.

The Phase II investigated the clinical efficacy of BYL719 and consisted of an open label, randomized Phase II part investigating BYL719 in combination with cetuximab compared to cetuximab alone in patients resistant or intolerant to platinum and naïve to cetuximab (Scheme 1: Arm 1 and Arm 2), and a non-randomized Phase II part Scheme 2: Arm 3. In addition, patients who experienced disease progression in Arm 2 (cetuximab) were allowed to switch to the combination regimen (cross-over, Arm 2B). The safety of the BYL719 in combination with cetuximab was also further characterized in Arms 1, 2B and 3.

Patients were treated until progression of disease), unacceptable toxicity, or withdrawal of informed consent, whichever occurred first (except for phase II Arm 2 had the opportunity to crossover to the combination treatment (Arm 2B). In the follow-up period all patients had to complete the safety follow-up assessments within 30 days after the last dose of the study treatment. Patients who did not have disease progression at the time of discontinuation of study treatment were radiologically followed for disease status until disease progression, initiation of subsequent anticancer therapies, or death, whichever occurred first. In addition, all patients enrolled in Phase II were followed for survival.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Therapeutic targeting of cancers with loss of PTEN function.
   Dillon LM, Miller TW. · · 2014 · cited 194× · PMID 24387334 · DOI 10.2174/1389450114666140106100909
2. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design.
   Massacesi C, Di Tomaso E, Urban P, Germa C, et al · · 2016 · cited 171× · PMID 26793003 · DOI 10.2147/ott.s89967
3. Clinical update on cancer: molecular oncology of head and neck cancer.
   Suh Y, Amelio I, Guerrero Urbano T, Tavassoli M. · · 2014 · cited 132× · PMID 24457962 · DOI 10.1038/cddis.2013.548
4. Genomic landscape of human papillomavirus-associated cancers.
   Rusan M, Li YY, Hammerman PS. · · 2015 · cited 109× · PMID 25779941 · DOI 10.1158/1078-0432.ccr-14-1101
5. Targeting the RAS oncogene.
   Takashima A, Faller DV. · · 2013 · cited 95× · PMID 23360111 · DOI 10.1517/14728222.2013.764990
6. Human Papillomavirus-Associated Oropharyngeal Cancer: Defining Risk Groups and Clinical Trials.
   Bhatia A, Burtness B. · · 2015 · cited 94× · PMID 26351343 · DOI 10.1200/jco.2015.61.2358
7. Cetuximab-Containing Combinations in Locally Advanced and Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.
   Taberna M, Oliva M, Mesía R. · · 2019 · cited 84× · PMID 31165040 · DOI 10.3389/fonc.2019.00383
8. Clinical implications of the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in progression and treatment of non-small cell lung cancer.
   Quan Z, Yang Y, Zheng H, Zhan Y, et al · · 2022 · cited 81× · PMID 36313041 · DOI 10.7150/jca.77619