The latest prospects of investigational drugs for head and neck cancer

KEYWORDS:

• Chemotherapy
• drug development
• head and neck cancer
• systemic treatment
• targeted therapy

1. Introduction

Squamous-cell cancer of the head and neck (SCCHN) is often diagnosed at advanced stages which require systemic treatments [1–4]. Current standards, both for curative and recurrent and/or metastatic (R/M) setting, involve cytotoxic chemotherapy agents (mainly platinum compounds), the EGFR inhibitor cetuximab, and the immune checkpoint inhibitors (ICIs) nivolumab and pembrolizumab (the latter two recently approved by the FDA, but not globally). The long-term survival rates are still low; and with the current treatment modalities, the upper limit of toxicity seems to be reached [5].

While we briefly focus on the current landscape of the clinical trials involving targeted drugs being investigated for the treatment of SCCHN, comprehensive information about the substances, their mechanisms of action, and results of previous trials can be obtained from recently published reviews [6–8].

Table 1 provides an overview of the agents which continued to be investigated in clinical trials in past 2 years. Worth to note, only 5% of the drugs, which show an anticancer activity in the early phases of development, later demonstrate a success in the phase III trials [9].

Table 1. Overview of agents investigated in the last 2 years for squamous cell cancer of the head and neck.

Category and agent	Target/mechanism of action	Setting and highest development phase
		R/M	CRT	I/N	A/C/M
Anti-EGFR
Cetuximab	Anti-EGFR mAB	III	III	III
Panitumumab	Anti-EGFR mAB	III	III	I
Zalutumumab	Anti-EGFR mAB	III	III
Nimotuzumab	Anti-EGFR mAB	II	III	II
Erlotinib	Anti-EGFR TKI	II	III	II	III
Gefitinib	Anti-EGFR TKI	III	II	II
Lapatinib	Anti-EGFR TKI	II	III	II
Afatinib	Anti-EGFR TKI	III	III	II	III
Dacomitinib	Anti-EGFR TKI	II	I
Sym004	Mixture of two anti-EGFR mABs	II
Tarloxotinib	Anti-EGFR TKI under hypoxia	II
Drugs targeting VEGFR and PDGFR
Sorafenib	TKI of VEGFR, PDGFR, Raf, c-kit	II
Bevacizumab	mAB targeting VEGFR	III	II	II
Sunitinib	TKI of VEGFR, PDGFR, c-kit, RET, CSF-1R, FLT3	II	I	II
Vandetanib	TKI of VEGFR-2, EGFR, and RET	II	I		II
Cyclooxygenase-2 inhibitors
Celecoxib	Inhibition of COX-2	II	III	II	III
Immune checkpoint modulators
Nivolumab	Anti-PD-1 mAB	III	II	I
Pembrolizumab	Anti-PD-1 mAB	III	II	II
Durvalumab	Anti-PD-L1 mAB	III
Atezolizumab	Anti-PD-L1 mAB	I
Ipilimumab	Anti-CTLA-4 mAB	III	I	I
Tremelimumab	Anti-CTLA-4 mAB	III
Urelumab	Anti-PD-L1 mAB	I
PF-04518600	Anti-OX40 (CD134) mAB	I
MEDI6469	Anti-OX40 (CD134) mAB			I
Utomilumab	Anti-4-1BB (CD-137) mAB	I
Cytokines
IMO-2055	Immune stimulation via TLR9	II
Motolimod	Immune stimulation via TLR8	II		I
Leukocyte Interleukin injection	Immune stimulation			III
IRX-2	Immune stimulation			II
IL-12	Immune stimulation	II
IL-15	Immune stimulation	I
Adoptive T-cell therapies	Adoptive tumor infiltrating T cells	II
Cancer vaccines
GL-0817	MAGE-A3				II
ADXS11-001	HPV E7	II		II
P16_37-6	p16(INK4a)	II
ISA101	HPV16	II
Drugs targeting PI3K/AKT/mTOR/PTEN
Everolimus	mTOR	II	II	II	II
PX-866	PI3K	II
BYL719	PI3K	II	I	II
Buparlisib	PI3K	II	I
Sirolimus (rapamycin)	mTOR	II		II
Temsirolimus	mTOR	II
Drugs targeting Src
Saracatinib	Src, Bcr-Abl TKI	II
Dasatinib	Src, PDGFR, Bcr-Abl, c-Kit TKI	II	I	I
Drugs targeting HGF/cMET pathway
Tivantinib	cMET TKI	II
INC280	cMET TKI	II
Glesatinib	cMET TKI	I
Ficlatuzumab	Anti-HGF mAB	I	I
Golvatinib	cMET TKI	I
LY2801653	cMET TKI	I
Crizotinib	cMET TKI	II
Cabozantinib	cMET, VGEFR2 TKI	II
Ruxolitinib	JAK1 and -2	0
Histone deacetylase inhibitors
CUDC-101	Histone deacetylase	I	I
Vorinostat	Histone deacetylase	II	I
Romidepsin	Histone deacetylase	II
Panobinostat	Histone deacetylase	I	I
Valproic acid	Histone deacetylase	II	II		0
MEK inhibitors
Trametinib	MEK1 and -2			II
Selumetinib	MEK1 and -2	I
Drugs inducing the apoptotic pathway
Debio 1143	Second mitochondria-derived activator of caspase		II
Cyclin-dependent kinase inhibitors
Palbociclib	CDK4 and -6	II	II
Prexasertib	CHK1	I	I
Drugs targeting aberrant p53
AZD-1775	CDK2	II	I	I
NOTCH inhibitors
Ridaforolimus	NOTCH	I
IPI-926	NOTCH	I
WNT974	Porcupine	II
PARP inhibitors
Olaparib	DNA damage repair via PARP-1		I
Proteosome inhibitors
Bortezomib	NF-kB inactivation via blocking the IkB degradation	II	I
Hsp90 inhibitors
Ganetespib	Hsp90			I
AT13387	Hsp90		I
Viral therapies
Reolysin	Oncolytic virus exclusively replicating in cancer cells	III
Drugs to overcome hypoxia
Nimorazole	Reduction via ionization causing oxidative DNA damage		III
Tarloxotinib	Anti-EGFR TKI under hypoxia	II

A/C/M: adjuvant chemotherapy, chemoprevention, or maintenance; CRT: concomitant chemoradiotherapy; EGFR: epidermal growth factor receptor; I/N: induction or neoadjuvant; mAB: monoclonal antibody; R/M: Recurrent and/or metastatic disease which is deemed as uncurable; TKI: tyrosine kinase inhibitor.

2. R/M setting

Currently, the commonly used standard treatment for the R/M SCCHN is the EXTREME regimen, which consists of a triplet of a platinum, cetuximab, and fluorouracil [3]. Despite the success of cetuximab, efforts trying to show an overall survival (OS) benefit using other EGFR-targeting agents failed to show similar or superior results. There are still ongoing studies with various agents targeting EGFR pathway while newer agents like tarloxotinib and sym004 are being tested in their earlier development phases.

The last 2 years showed a rapid emergence of data about ICIs, which target PD-1, PD-L1, CTLA-4, CD134, or CD137. Recently, the highest level of evidence came from the phase III CheckMate 141 trial comparing anti-PD-1 monoclonal antibody (mAB) nivolumab with a monotherapy of investigators choice (methotrexate, cetuximab, or docetaxel) in the platinum-refractory R/M SCCHN. Without showing a significant improvement in progression-free survival, nivolumab significantly increased the primary end point OS compared to drug of investigators’ choice (7.5 vs. 5.1 months) [4]. The results of the phase I KEYNOTE-012 trial showed an overall response rate of 18% and a relatively safe toxicity profile [10,11]. Various phase III trials with other ICIs in the first- and second-line treatment of R/M SCCHN are ongoing. To establish the ICIs as a standard in the first-line treatment of R/M SCCHN, the results of the phase III trials comparing them with the standard EXTREME regimen are awaited (NCT02358031, NCT02551159, NCT02741570, NCT02551159).

3. Combining drugs with radiotherapy

For two decades, the platinum-based compounds still remain as standard drugs to be combined with radiotherapy in locally advanced SCCHN. Cetuximab, one of the first anti-EGFR mABs, showed success by increasing the loco-regional control and OS [2]. However, no superiority or non-inferiority of cetuximab to platin-based chemotherapy could be shown. Recently, presented results of the GORTEC 2007-01 (NCT00609284) study showed significant improvement in progression-free survival and loco-regional control when carboplatin and fluorouracil were added to concomitant cetuximab and radiotherapy. However, with a similar but opposite design, the previously published RTOG 0552 (NCT00265941) did not reveal a similar effect when cetuximab was added to cisplatin and radiotherapy. These findings suggest that the positive effect of cetuximab is dominated by the platinum compounds. Therefore, cetuximab remains as an alternative for patients who cannot tolerate conventional chemotherapy. Since the success of cetuximab, no other targeted agent showed any benefit when combined with radiotherapy alone or in combination with cytotoxic chemotherapy. Efforts to demonstrate a positive effect or non-inferiority with less toxicity through strategies targeting EGFR are ongoing.

Another promising approach is the combination of hypoxic cell sentisizers with radiation with or without chemotherapy. Phase II DAHANCA 18 trial [12] showed promising activity without markedly increased toxicity through the combination of nimorazole, weekly cisplatin, and accelerated radiotherapy. The ongoing phase III EORTC 1219 trial (NCT01880359) is expected to provide a definitive answer to this intriguing question.

With the increasing interest in ICIs, phase III trials combining these agents with various other agents are being designed. To our knowledge, all of them are planned to contain 6–12 months maintenance phases without any supporting evidence.

4. Induction/neoadjuvant treatment

Despite much effort and resource put into numerous randomized phase III trials investigating the potential benefit of systemic treatment prior definitive treatment with cytotoxic or targeted agents, no advantage over chemoradiotherapy or surgery is reported so far. The only study, which showed a benefit, was only presented as a congress abstract more than 2 years ago [13].

Currently, there are ongoing studies in advanced development phases involving targeted agents in the induction/neoadjuvant setting. The present interest is particularly in substances targeting the EGFR or PI3K/mTOR pathways, ICIs, and immune-stimulant cytokines.

5. Adjuvant/chemoprevention/maintenance treatment

There is no clear distinction among the definitions under this category. Most investigators tend to use the term ‘adjuvant,’ if the systemic treatment is administered after the definitive treatment (i.e. surgery or radiotherapy), which is administered in a few number of cycles in a period of weeks to few months. Maintenance treatments continue over many months to years. The expression ‘chemoprevention’ is used both for treatment-naive high-risk patients with premalignant lesions (NCT00402779, NCT01414426, NCT00101335), or in the posttreatment setting (NCT00570232, NCT02608736, NCT00934739) [14].

Trials under this category are either ongoing or completed showing no benefit due to their plausibility in terms of tolerability/effectiveness. Most of them were designed with cyclooxygenase-2 inhibitors and EGFR/VEGFR tyrosine kinase inhibitors (TKI). Agents under other categories are being currently tested in earlier development phases. It is also worth to note that most of the new clinical trials involving anti-EGFR TKIs and ICIs in curative setting contain a maintenance part ranging from 6 to 12 months.

6. Conclusion

A wide variety of targeted agents are under development in different treatment settings of SCCHN. Beside the well-established value of conventional chemotherapeutics, anti-EGFR strategy showed a positive value without surpassing the effect of platinum-based compounds in terms of tumor control and survival benefit. Recently, ICIs proved their efficacy compared to previously established single agents in R/M setting. However, the results of head-to-head comparisons to the well-established EXTREME regimen are pending. In parallel, development of other agents for SCCHN is ongoing in a relatively slower pace.

7. Expert opinion

The current landscape of the drug development for SCCHN is strongly influenced by the general trends in major solid tumor types. Most new drugs are being tested on previously heavily treated patients whose tumors likely developed multiple resistance mechanisms and exhausted reserves to cope with toxicities. It is promising to observe an increase in the number of window-of-opportunity trials in the treatment-naive patients where the risk of hampering the treatment compliance is considerably lower. In presurgical setting, they also provide invaluable information about potential biomarkers. Early development of new substances in combination with radiotherapy should also be tested in parallel without first waiting for the mature phase III data to emerge in the R/M.

The combination of ICIs with cytotoxic chemotherapeutics may widen the therapeutic window. On the other hand, the immune-suppressing effect of these conventional chemotherapeutics may hamper the effect of the immune response. For example, with a less conventional approach, a new multicenter phase III trial is underway, where an ICI will be combined with a targeted agent, concomitant to radiotherapy in the curative setting of SCCHN (details not officially disclosed). Multiple early interim analyses about the safety and efficacy are planned. ICIs are considered as relatively safe with favorable toxicity profiles and less impact on quality of life compared to other standard agents/combinations [3–5,11]. Their distinct toxicity profile may be amplified or altered with new drug combinations. Special care is required in this uncharted territory. Worryingly, in the current competitive drug development environment, the pharmaceutical industry is increasingly skipping the well-established clinical trial phases by extrapolating safety/efficacy data from dissimilar treatment settings.

Apart from the success of ICIs, another promising class consists of agents targeting the PI3K axis. Currently, a lot of investment is made in the phase I/II trials involving these group of agents. With a convincing biological rationale, some completed studies showed promising activity (NCT01283334, NCT01852292, NCT01527877) worth to be tested in an advanced phase. Additionally, the anticipated results of the EORTC 1219 will define whether the hypoxic cell sensitizers will become a part of the internationally accepted standard of care. So far, as previously mentioned by Overgaard, treatments targeting hypoxia were ‘adored and ignored’ [15].

Last but not least, the concept ‘maintenance therapy’ is not based on solid clinical evidence which indicate the necessity of such lengthy schedules. If a trial involving such an extended maintenance treatment defines a future standard of care, it is obvious that the pharmaceutical industry will not support any trials with a non-inferiority design to investigate the possible futility of the maintenance part following the curative treatment. In this regard, the ethical and financial responsibilities of the physicians leading the field of research and the policy makers involved in health care are worth to be reminded.

Declaration of interest

O. Elicin and M. Ozsahin have received consultation fees from Merck Group for attending advisory board meetings. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgments

We thank Dr. Nikola Cihoric for sharing the database of http://clinicaltrial.co/.