What are the new drugs for Laryngeal Cancer?

Overview of Laryngeal Cancer

Laryngeal cancer is a malignancy that arises from the tissues of the larynx, the anatomical “voice box” in the upper airway. Most laryngeal cancers are squamous cell carcinomas (SCCs) that can be further subdivided into glottic, supraglottic, and subglottic cancers. Epidemiologically, laryngeal cancer represents a considerable portion of head and neck malignancies and continues to significantly affect quality of life. Though overall incidence trends vary by geographical region, the disease is closely linked with risk factors such as tobacco use, alcohol consumption, and exposure to environmental carcinogens. Studies based on population databases in countries including Germany and Poland have documented that although there have been gradual improvements in treatment outcomes, the mortality in advanced stage laryngeal carcinoma remains high. The demographic profile shows that most patients are in their sixth to seventh decades of life and the majority are male. In addition to the classic epidemiological characteristics, increasing attention is now paid to molecular profiling to better understand the heterogeneity of these cancers and to guide new targeted and immune‐based therapies.

Current Treatment Options

Traditionally, treatment for laryngeal cancer has been based on a combination of surgery, radiotherapy, and chemotherapy. For early‐stage disease, options such as transoral laser microsurgery or partial laryngectomy in combination with radiotherapy can be curative while preserving laryngeal function. For advanced disease—especially stage III or IV tumors—total laryngectomy combined with adjuvant radiotherapy or chemoradiotherapy has served as the standard; however, this traditional approach comes at the cost of significant morbidity and permanent loss of normal voice. As head and neck oncology evolved, non–surgical laryngeal preservation protocols emerged, particularly with the introduction of concurrent chemoradiotherapy regimes. More recently, the advent of biological therapies has led to the inclusion of targeted agents in the treatment armamentarium for head and neck cancers, including laryngeal cancer. Despite these advances, overall survival improvements have been modest across many series, and the pursuit of innovative drugs remains central to improving both efficacy and quality of life in these patients.

New Drug Developments

In recent years the treatment landscape for head and neck cancers—including laryngeal carcinoma—has been undergoing a gradual transformation, fueled in part by the introduction of novel immunotherapeutic agents and compounds derived from natural sources. Although the majority of research and regulatory approvals in this area target head and neck squamous cell carcinoma (HNSCC) as a group, many of these advances apply specifically to laryngeal cancer given its biological overlap with other subsites.

Recently Approved Drugs

A number of new drugs approved for HNSCC in the past decade have begun to influence laryngeal cancer management. Among these, the most prominent are the immune checkpoint inhibitors. Notably, pembrolizumab (commonly marketed as Keytruda) and nivolumab (Opdivo) have gained acceptance in the treatment of recurrent and metastatic head and neck cancers, and their indications often encompass laryngeal carcinoma as it falls under the broader umbrella of HNSCC.

Pembrolizumab, a humanized anti–PD-1 monoclonal antibody, is now widely used for cases of advanced HNSCC that are refractory to standard platinum-based therapies. In in vitro studies, upregulation of compounds such as hsa-miR-128a has been shown to potentiate the cytotoxic effects of pembrolizumab on laryngeal cancer cell lines. This approach not only underscores pembrolizumab’s role as a new drug but also emphasizes how emerging biomarkers can enhance its efficacy. Similarly, nivolumab has been approved as a second-line treatment for recurrent or metastatic disease in patients with HNSCC, including laryngeal cancer. New regulatory documents and clinical trial databases suggest that these drugs now play a central role in organ preservation approaches for laryngeal cancer patients, thereby sparing some patients from more mutilating surgeries.

Some of the recently approved agents also include drugs that have shown promise in other head and neck locations and may be repurposed for laryngeal cancer. While agents like cetuximab have been in use for several years as epidermal growth factor receptor (EGFR) inhibitors and continue to be a part of combination regimens, their status as “new” drugs is less clear since they are already well established. Instead, the focus has shifted toward the novel immune checkpoint inhibitors which have received priority review status from regulators such as the FDA and EMA. These approvals have been accompanied by robust efficacy signals in Phase III trials of HNSCC, and their applicability to laryngeal cancer is being increasingly accepted by the oncology community.

In addition to checkpoint inhibitors, some natural compounds with potential antitumor activity in laryngeal carcinoma have emerged from preclinical evaluations. For example, galangin—a flavonoid extracted from plants such as Alpinia officinarum—has recently been investigated for its antiproliferative effects in human laryngeal cancer cell lines. Galangin has been shown to provoke apoptosis and induce autophagy via interference with key signaling cascades like PI3K/AKT; although it is not yet approved by regulatory bodies, its promising activity in preclinical studies positions it as a novel candidate that could be developed further.

Another emerging agent is corilagin, a natural phenolic compound derived from several medicinal plants, that has been studied for its role in hampering cell proliferation and promoting apoptosis in laryngeal cancer cells. Although the clinical pathway for these natural compounds is still in the early investigational stage, they represent an important line of repurposing and new drug discovery approaches that are cost effective and may have fewer side effects compared to conventional chemotherapeutics.

Drugs in Clinical Trials

While the currently approved drugs in the immunotherapy sector have rapidly reshaped the treatment paradigm, several investigational agents are being evaluated in clinical trials specifically for laryngeal cancer. Numerous Phase I/II trials are now testing combinations of immune checkpoint inhibitors with either targeted therapies or conventional chemoradiotherapy to improve organ preservation and overall survival. The rationale for these trials is supported by robust preclinical data—evidenced, for example, by studies enhancing the sensitivity of cancer cells to pembrolizumab by modulating microRNA levels. Other novel drugs include new small-molecule inhibitors targeting specific oncogenic pathways. Although the EGFR-targeted therapies continue to be part of standard regimens, newer agents aim to combine EGFR inhibition with additional blockade of downstream signaling pathways to overcome resistance.

Beyond the immunologic realm, early-phase trials are underway with compounds that have shown promise in other tumor types. For example, in silico drug repositioning studies have predicted that certain kinase inhibitors, although originally designed for other cancers, may have activity against laryngeal carcinoma via a compensatory targeting effect on tumor metabolism and survival pathways. These approaches are leveraging advanced bioinformatics analyses of gene expression profiles and network-based predictions to repurpose older drugs for a new indication in laryngeal cancer. Although definitive trial results are not yet available, preliminary data indicate a potential benefit in selecting drugs that provide the “opposite effect” on dysregulated disease genes, a strategy that could soon be tested in early clinical trials.

New combinatorial regimens involving conventional cytotoxic agents with nontraditional compounds (such as natural bioactives or epigenetic modifiers) are also being explored. These trials aim to address the persistent problem of chemoresistance in advanced laryngeal cancer. For instance, studies have examined combining established drugs with novel agents that can either modulate the tumor microenvironment or target cellular energy metabolism, thereby sensitizing the tumor to established treatments. Such trials are in early stages but offer promise by integrating the benefits of synergistic combinations with improved toxicity profiles.

Mechanism of Action

A deep understanding of how new drugs act is pivotal in developing treatments that are both efficacious and safe for patients with laryngeal cancer. The emerging therapies can be broadly categorized into targeted therapies and immunotherapies, each with distinct mechanisms that have been the focus of both preclinical and clinical investigations.

Targeted Therapies

Targeted therapies aim to exploit specific abnormalities in cancer cells that drive tumor growth and survival. In laryngeal cancer, which is molecularly heterogeneous, several oncogenic pathways such as the EGFR and the PI3K/AKT/mTOR pathways are known to be dysregulated. Although cetuximab has been used for many years as an EGFR inhibitor, newer compounds are being developed to target these pathways more precisely. For example, preclinical studies involving natural compounds like galangin have demonstrated that they can inhibit the PI3K/AKT pathway, triggering apoptosis and autophagy in laryngeal cancer cells. Such targeted agents, by modulating signal transduction, offer the dual benefit of inhibiting tumor growth while potentially reducing toxicity to normal tissues.

Furthermore, network‐based in silico methods are being used to predict molecules that might counteract oncogenic drivers by “inverting” the signature of disease genes. These methods take into account the effect types and directions—in other words, whether the drug’s action is inhibitory or activating relative to the dysregulated gene expression seen in cancer. Although these approaches remain largely investigational, they represent a trend toward precision medicine where a drug is chosen not solely for its known pharmacologic class but because it specifically counterbalances the tumor’s molecular phenotype.

Immunotherapy

Immunotherapy has revolutionized the treatment of various malignancies, and its application in head and neck cancers, laryngeal cancer included, is now well established. The primary agents in use target the programmed cell death protein 1 (PD‑1) pathway. Pembrolizumab, for example, binds to PD‑1 on T cells and blocks its interaction with PD‑L1 and PD‑L2, thereby releasing the “brakes” on the immune system and facilitating an antitumor immune response. Nivolumab, another anti–PD‑1 agent, acts in a similar manner and provides a novel therapeutic option, especially in the salvage setting for patients who have progressed on chemoradiotherapy.

In addition to single‐agent checkpoint blockade, combination regimens are under active investigation. Preclinical models have demonstrated that modifying gene expression—such as by upregulating hsa‑miR‑128a—can enhance the sensitivity of laryngeal cancer cells to pembrolizumab. Combination strategies often seek to overcome resistance mechanisms by simultaneously targeting the immune checkpoint and other pathways involved in tumor immunosuppression or survival. Another potential immunotherapeutic approach is to combine checkpoint inhibitors with agents that modify or ‘re‐educate’ the tumor microenvironment, essentially making it more amenable to an immune attack.

Mechanistically, the immune checkpoint inhibitors offer a systemic approach: they not only target the primary tumor cells but also promote a more robust immune surveillance that may help eliminate micrometastatic disease. Their mechanism differs fundamentally from cytotoxic drugs in that they harness the body's immunologic capacity rather than directly killing tumor cells, and—if the appropriate biomarkers are used—they can be tailored to patient subsets that show upregulation of PD‑L1 or other immunosuppressive molecules.

Clinical Effectiveness and Safety

Efficacy Data from Trials

The clinical trial data for new drugs in the context of laryngeal cancer have primarily emerged from studies in head and neck squamous cell carcinoma populations. In randomized controlled trials and observational studies, immune checkpoint inhibitors such as pembrolizumab and nivolumab have demonstrated improvements in overall survival (OS) and progression-free survival (PFS) compared to standard chemotherapeutic regimens in recurrent or metastatic settings. For example, pivotal trials that included patients with laryngeal cancers have shown that pembrolizumab can yield response rates that are meaningful in salvage settings, with survival benefits in a subset of patients who previously failed conventional therapies.

It is important to note that the efficacy of these agents is not uniform across all patients. Biomarker studies have indicated that certain molecular features—such as increased miR‑128a in laryngeal cancer cells—can correlate with enhanced responses to pembrolizumab, suggesting that patient selection based on molecular profiling is critical for improving outcomes. Meanwhile, preclinical data for novel natural compounds like galangin and corilagin have demonstrated strong antiproliferative effects and induction of apoptosis in laryngeal cancer cell lines. Although these are not yet approved drugs, the promising preclinical efficacy encourages further early‐phase trials to assess their clinical potential.

Furthermore, combination regimens, whether they combine immunotherapy with chemotherapy or target both immune and oncogenic pathways, are being actively explored. Trials combining checkpoint inhibitors with conventional chemoradiotherapy have reported encouraging responses, particularly in organ preservation strategies where maintaining laryngeal function is paramount. Even though these combinations may be experimental, early efficacy signals are promising and are being evaluated with endpoints that include not only survival but also patient quality‐of‐life measures—a crucial consideration given the functional importance of the larynx.

Safety Profiles and Side Effects

Safety is a critical element in the evaluation of new drugs for laryngeal cancer, especially as treatments for head and neck cancers carry risks not only from the direct effects of cytotoxic agents but also from the potential for immune-mediated adverse events. Immune checkpoint inhibitors like pembrolizumab and nivolumab are generally associated with a different toxicity profile compared with traditional chemotherapy. Common side effects include fatigue, rash, and endocrine abnormalities (such as hypothyroidism), while severe immune-related adverse events, though rarer, can include pneumonitis, colitis, and hepatitis. The safety data from key trials indicate that, although these drugs may lead to discontinuation in a subset of patients, their overall side-effect profile is manageable and often preferable to the morbidity associated with surgery or high-dose chemoradiotherapy.

In contrast, novel agents such as galangin and corilagin are currently under investigation and, as natural compounds, they might be expected to have fewer or less severe side effects. Preclinical studies in laryngeal cancer models suggest that these compounds can induce cell death without significant toxicity to normal tissues. However, as many of these agents are in the early stages of development, comprehensive safety profiles from Phase I/II trials are still pending.

With the advent of immunotherapy, an area of active research is identifying predictive biomarkers not only for efficacy but also for adverse events. For instance, studies are exploring whether baseline expression levels of immune checkpoints or specific microRNAs could predict susceptibility to immune-related toxicities. This personalized approach might help clinicians balance the benefits and risks of therapy more effectively.

Regulatory and Market Considerations

Approval Status by Regulatory Bodies

From a regulatory perspective, the approval of drugs for the treatment of laryngeal cancer is currently managed under the broader indication of head and neck squamous cell carcinoma. As such, major regulatory bodies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved immune checkpoint inhibitors like pembrolizumab and nivolumab for patients with recurrent or metastatic HNSCC. These approvals generally come after extensive evaluation of randomized controlled trials showing statistically significant improvements in survival endpoints. Priority reviews and breakthrough therapy designations have been granted for these agents in many oncology indications, reflecting the urgent need for effective therapies in advanced disease settings.

Other drugs—such as targeted natural compounds or repurposed agents identified by in silico analyses—have not yet completed the regulatory process for laryngeal cancer specifically. Nevertheless, in the era of drug repositioning, many ongoing trials are evaluating the efficacy of old compounds for new indications based on their mechanism and preclinical activity. The repurposing strategy is particularly attractive in cancer therapy given the high costs and the long timelines (often 10–15 years) required for de novo development. In several synapse sources, authors stress that new compounds emerging either from novel synthetic methods or through computational repositioning models must still pass through early-phase evaluation before they can be approved.

Moreover, the regulatory reviews today increasingly emphasize not only safety and efficacy but also an improvement in patient quality of life. New data from immunotherapy and targeted trials are scrutinized both for survival improvement as well as for the lower rate of severe adverse events compared to conventional treatments. For instance, pembrolizumab has been evaluated in multiple types of trials with companion diagnostics used to identify patients most likely to benefit from therapy; similar strategies are now being considered for investigational agents in laryngeal cancer.

Market Availability and Access

Even after regulatory approval, market availability of new drugs can be impacted by several factors, including pricing, reimbursement policies, and regional differences in access. In the United States and Europe, immune checkpoint inhibitors have increasingly become part of standard treatment algorithms for head and neck cancers, and their use in laryngeal cancer is typically integrated into multidisciplinary treatment plans. However, cost remains a significant barrier in many countries—particularly for therapies such as pembrolizumab and nivolumab which, despite their clinical benefits, command premium prices.

Market access programs and the negotiation of pricing with health systems and insurers are now part of the drug development cycle. The availability of biosimilars and parallel efforts in drug repurposing may help lower these costs. Natural compounds and novel small‐molecule inhibitors that show promising efficacy in early trials may eventually offer a more cost-effective approach if they can be brought to market with lower research and development costs.

Furthermore, given that laryngeal cancer is often grouped under the umbrella of head and neck cancers, market access considerations for treatments in this area are influenced by guideline recommendations from bodies such as the National Comprehensive Cancer Network (NCCN) as well as by real‐world evidence emerging from registries and population‐based studies. In many cases, the rapid learning platforms and network meta-analyses discussed in recent papers are being used to compare outcomes across treatments in real-life settings, guiding payers in reimbursement decisions and clinicians in treatment selection. These efforts aim to ensure that the most effective and safe drugs reach the patients who need them while keeping costs in check.

Conclusion

In conclusion, the new drugs for laryngeal cancer represent a transition from traditional cytotoxic agents and radical surgical approaches to more effective, targeted, and immunotherapeutic strategies. The introduction of immune checkpoint inhibitors—specifically agents such as pembrolizumab (Keytruda) and nivolumab (Opdivo)—has revolutionized the treatment paradigm for head and neck squamous cell carcinoma, which includes laryngeal cancer. Preclinical studies have shown that the efficacy of pembrolizumab can be enhanced by modulating molecular factors (e.g., hsa‑miR‑128a), and these studies pave the way for personalized immunotherapy. In addition, natural compounds like galangin and corilagin, which act via targeted inhibition of survival pathways such as PI3K/AKT and induce apoptosis, are emerging as promising candidates in early-phase clinical trials. Although many investigational agents are still in the clinical trial pipeline, the trend points toward combination regimens that integrate immunotherapy with targeted molecules and conventional treatment—to not only prolong survival but also improve quality of life and organ preservation in laryngeal cancer patients.

Mechanistically, the new drugs can be broadly divided into targeted therapies that aim to disrupt abnormal oncogenic signaling and immunotherapies that harness the patient’s own immune system to fight the cancer. Safety profiles for these agents tend to differ from conventional chemotherapy; for instance, immune checkpoint inhibitors generally have a tolerable safety profile with manageable immune-related adverse events, although careful patient selection is crucial. Efficacy data from several pivotal trials support these novel approaches, with improved survival data and better organ preservation outcomes being demonstrated, albeit often in heterogeneous patient populations that include laryngeal cancers as a subset.

From a regulatory standpoint, key regulatory bodies such as the FDA and EMA have already approved major immunotherapeutic agents for head and neck cancers, which effectively cover laryngeal cancer. These approvals are accompanied by breakthrough designations and priority review statuses, emphasizing their significant clinical benefit and the unmet need in this disease area. Meanwhile, market availability and access remain challenging due to high costs that are an intrinsic part of advanced biologic therapies; however, the drive toward drug repurposing and the development of cost-effective natural compounds offer potential solutions for broader access in the future.

In summary, the current landscape of new drugs for laryngeal cancer is dominated by immunotherapeutic agents such as pembrolizumab and nivolumab, which have been rigorously evaluated in clinical trials and approved by leading regulatory agencies. Meanwhile, new investigational drugs—ranging from novel small-molecule inhibitors to plant-derived compounds—are in various stages of clinical trials, aiming to overcome resistance and reduce treatment-related toxicities. Emerging insights into the molecular mechanisms of laryngeal cancer, combined with advanced predictive and computational methods, are paving the way for personalized therapies that may eventually transform the standard of care. Ultimately, these developments offer the hope of not only increasing survival but also preserving laryngeal function and improving quality of life for patients, while regulatory and market initiatives strive to balance innovation with cost-effectiveness. This multifaceted approach underscores the importance of continued research and collaboration among scientists, clinicians, and industry partners to optimize treatments for this challenging disease.

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