Advancements in the Development of Targeted Agents for Head and Neck Squamous Cell Carcinomas

CURRENT TREATMENT LANDSCAPE OF SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Head and neck squamous cell carcinoma of the head and neck (HNSCC) most frequently develops in the mucosal epithelium of the oral cavity, pharynx, and larynx.¹ Histological progression of the disease begins with epithelial cell hyperplasia, followed by dysplasia (mild, moderate, and severe), carcinoma in situ, and ultimately, invasive carcinoma.

Some patients may present with leukoplakia or erythroplakia, which are premalignant lesions that may eventually progress to invasive cancer. However, the majority of patients present with advanced stage HNSCC without a clinical history of a premalignancy, and approximately 12% of HNSCC cases are diagnosed at the metastatic stage.^1-3 An estimated 10% to 20% of patients treated for early-stage HNSCC experience recurrence, as well.^1,2

Patients with stage I or stage II HNSCC are typically treated with single-modality surgery or radiotherapy, which yield 5-year survival rates of approximately 90% and 70%, respectively.² Patients with advanced and/or recurrent or metastatic (R/M) HNSCC typically require multiple treatment modalities, but, historically, few therapeutic options have been available for these patients.³

Although immunotherapies have entered the treatment landscape within the past 5 years, prognosis for patients with advanced and/or R/M HNSCC remains poor.^2,3 Only 30% of patients with advanced HNSCC are cured.³ Furthermore, HNSCC diseases are diverse and complex, and they manifest high levels of intertumoral and intratumoral heterogeneity; consequently, therapeutic responses vary widely among tumor subtypes, regardless of their clinical stages.⁴

As discussed in the previous article, “Exploring the evolving molecular landscape of head and neck squamous cell carcinomas,” advances in genomic profiling have enabled the discovery of oncogenic mutations, such as mutated HRAS, for which novel targeted therapeutics can be developed.⁵ Furthermore, next generation sequencing (NGS) techniques can be used to screen for the presence of these mutations in patient tumors to help inform clinicians’ treatment choices and identify patients who are most likely to benefit from targeted therapies.^5,6

This article will provide an overview of the efficacy and safety of FDA–approved targeted therapies for HNSCC, as well as therapeutic gaps that still remain; discuss the clinical development of the farnesyltransferase (FTase) inhibitor (FTI) drug class with a focus on key results from tipifarnib clinical trials; and provide insights into other novel agents for which clinical trials are underway.

FDA-APPROVED TARGETED THERAPIES FOR HNSCC

The FDA has fully approved 3 targeted therapies for HNSCC: cetuximab, an EGFR inhibitor, and nivolumab and pembrolizumab, which are PD-1 checkpoint inhibitors.^7-12 Although cetuximab targets EGFR, and nivolumab and pembrolizumab target PD-1, their use as therapies for R/M HNSCC is not driven by biomarker information.^11-14 Table 1 summarizes key efficacy and safety data for cetuximab, nivolumab, and pembrolizumab, as well as for the investigational agent tipifarnib.^13-19

Cetuximab

In 2006, cetuximab became the first (and, for a decade, the only) targeted therapy approved to treat patients with HNSCC.^7,8 Cetuximab is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced HNSCC, in combination with platinum-based therapy with fluorouracil (FU) for the first-line treatment of patients with recurrent locoregional disease or metastatic HNSCC, or as a single agent for the treatment of patients with R/M HNSCC for whom prior platinum-based therapy has failed.⁷ These indications were based on the results of the following pivotal trials, respectively: BONNER (NCT00004227), a randomized, multicenter controlled trial that enrolled adult patients with locally or regionally advanced stage III or IV HNSCC; EXTREME (NCT00122460), an open-label, randomized, multicenter controlled trial that enrolled adult patients with recurrent locoregional disease or metastatic HNSCC; and EMR 62202-016, a single-arm, multicenter clinical trial of cetuximab monotherapy in adult patients with R/M HNSCC.^7,13,17,18

BONNER

The primary end point of the BONNER trial was duration of locoregional disease control; secondary end points included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety for patients treated with cetuximab plus radiation (n = 211) versus radiation alone (n = 213).¹⁷ The median duration of locoregional control was 24.4 months in patients treated with cetuximab plus radiation compared with 14.9 months in patients treated with radiation alone (HR for locoregional progression or death, 0.68; 95% CI, 0.52-0.89; P = .005). After a median follow-up of 54 months, the median OS was 49 months in patients treated with cetuximab plus radiation compared with 29.3 months in patients treated with radiation alone (P = .03). The most common grade 3 or 4 adverse events (AEs) that occurred in 10% or more of patients treated with cetuximab and radiation were mucositis (56%), dysphagia (26%), and radiation dermatitis (23%).

EXTREME

The primary end point of the EXTREME trial was OS for patients treated with cetuximab plus platinum-based therapy and FU (n = 222) versus the group given platinum-based therapy and FU (n = 220).¹⁸ The median OS was 10.1 months in patients given cetuximab plus platinum-based therapy and FU (95% CI, 8.6-11.2 months) versus 7.4 months in those given platinum-based therapy and FU (HR for death, 0.80; 95% CI, 0.64-0.99; P = .004).

The PFS and best response rates were among the secondary end points of the EXTREME trial. In patients treated with cetuximab plus platinum-based therapy plus FU, PFS was 5.6 months versus 3.3 months for patients treated with platinum-based therapy and FU alone (HR, 0.54; 95% CI, 0.43-0.67; P < .001 ).¹⁸ Overall best response to therapy was 36% (odds ratio, 2.33; 95% CI, 1.5%-3.6%; P < .001).

Most patients (82%, n = 179) treated with cetuximab plus platinum-based therapy and FU experienced a grade 3 or 4 AE.¹⁸ The most common grade 3 or 4 AEs occurring in 10% or more of patients in the group given cetuximab plus platinum-based therapy and FU included neutropenia in 49 patients (22%), anemia in 239 patients (13%), and thrombocytopenia in 24 patients (11%).

EMR 62202-016

EMR 62202-016 aimed to determine the scope of cetuximab activity in patients with R/M HNSCC who already progressed on platinum-based therapy by comparing the intent-to-treat efficacy data from previous phase 2 studies with a retrospective study of a similar group of patients who were treated outside of clinical trials.¹³ The primary end point was response to treatment, defined as the best confirmed response.

Response rates (which included complete response [CR] and partial response [PR]), median survival, and median progression were similar among patients treated cetuximab monotherapy (n = 103), cetuximab plus cisplatin or carboplatin (n = 96), or cetuximab plus cisplatin (n = 79).¹³ In the cetuximab group, 13% (95% CI, 7%-21%) of patients responded to treatment compared with 10% of both patients taking cetuximab plus cisplatin or carboplatin (95% CI, 5%-18%) and those taking cetuximab plus cisplatin (95% CI, 5%-18%). The median OS of patients in the cetuximab group was 5.9 months (95% CI, 4.9-7.1) compared with 6.1 months (95% CI, 4.9-7) in those using cetuximab plus cisplatin or carboplatin and 5.2 months (95% CI, 3.1-6) in patients given cetuximab plus cisplatin.

These results show that although cetuximab in combination with radiation or chemotherapy may significantly prolong OS compared with either radiation or chemotherapy alone in a front-line setting, OS rates are still low, and treatment response durations are short.^7,13,17,18 The efficacy of cetuximab monotherapy is also much lower than its efficacy in combination with chemotherapy or the efficacy of chemotherapy alone.¹³ Furthermore, most patients who are treated with cetuximab plus platinum-based therapy plus FU will experience severe AEs that could negatively impact their quality of life (QOL).¹⁸

PD-1 Checkpoint Inhibitors

Ten years after the approval of cetuximab for HNSCC, the FDA approved nivolumab, the first PD-1 checkpoint inhibitor indicated for patients with R/M HNSCC and disease progression or after platinum-based therapy.^9,10 This indication was based on the results of the pivotal CHECKMATE 141 trial (NCT02105636), a randomized, active-controlled, open-label study that enrolled patients with R/M HNSCC who experienced disease progression during or within 6 months of receiving platinum-based therapy administered in either the adjuvant, neoadjuvant, primary (unresectable locally advanced) or metastatic settings.^10,14

CHECKMATE 141

In CHECKMATE 141, patients were randomized 2 to 1 to receive nivolumab or investigator’s choice of cetuximab, methotrexate, or docetaxel.¹⁴ The primary outcome measure was OS. Median OS was 7.5 months in the nivolumab group (n = 240) versus 5.1 months in the investigator’s choice group (n = 121). Differences in PFS were not statistically significant between the 2 arms.

This study reported all-grade treatment-emergent AEs (TEAEs) that occurred in at least 5% of patients in either group. TEAEs occurred in 139 patients (58.9%) in the nivolumab group and in 86 patients (77.5%) in the investigator’s choice group.¹⁴ Grade 3 or 4 TEAEs occurred in 31 patients (13.1%) taking nivolumab and 39 patients (35.1%) taking the investigator’s choice. The most common grade 3 or higher TEAEs were fatigue (2.1%) and anemia (1.3%).

In 2019, the FDA approved another PD-1–blocking antibody, pembrolizumab, as a treatment for HNSCC.^11,12 It is indicated in combination with platinum and FU for the first-line treatment of patients with metastatic or unresectable, recurrent HNSCC; as a single agent for the first-line treatment of patients with metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1; or as a single agent to treat patients with R/M HNSCC and disease progression on or after platinum-containing chemotherapy.¹¹

These indications were based on results from the pivotal trials KEYNOTE-048 (NCT02358031), a randomized, multicenter, open-label, active-controlled trial to assess the OS and PFS of pembrolizumab as a first-line therapy in patients with metastatic or unresectable, recurrent HNSCC; and KEYNOTE-012 (NCT01848834), a multicenter, nonrandomized, open-label, multicohort study to evaluate the ORR in patients with R/M HNSCC.^11,12,15

KEYNOTE-048

The primary end points of KEYNOTE-048 were OS, defined as the time from randomization to death from any cause, and PFS, defined as the time from randomization to radiographically confirmed disease progression or death from any cause (whichever came first).¹⁵ Patients were randomized 1 to 1 to 1 to receive pembrolizumab monotherapy (n = 301), pembrolizumab plus chemotherapy (n = 281), or cetuximab plus chemotherapy (n = 300).

The median OS of patients treated with pembrolizumab alone was 11.6 months (95% CI, 5-13.6), compared with 10.7 months (95% CI, 9.3-11.7) in the group given cetuximab plus chemotherapy.¹⁵ The median PFS was estimated to be 2.3 months (95% CI, 2.2-3.3) in patients treated with pembrolizumab alone versus 5.2 months (95% CI, 4.9-6.0) in patients treated with cetuximab plus chemotherapy.

A subgroup analysis within KEYNOTE-048 evaluated the efficacy of pembrolizumab monotherapy versus pembrolizumab with chemotherapy or cetuximab with chemotherapy in patients whose tumors expressed high levels of PD-1 (as determined by a combined positive score [CPS] ≥ 20) and those without PD-1 expression (CPS ≤ 1).^11,15 Of the patients treated with pembrolizumab monotherapy, the median OS was 14.9 months (95% CI, 11.6-21.5) among patients with a CPS of at least 20 (n = 133) compared with 12.3 months (95% CI, 10.8-14.9) among patients with a CPS of 1 or less (n = 257). However, among all patients treated with pembrolizumab monotherapy, PFS was lower than among the groups of patients who received chemotherapy in combination with pembrolizumab or cetuximab. In addition, median OS and PFS were similar among patients treated with cetuximab and chemotherapy, regardless of PD-1 CPS score.

This study reported all-grade AEs of any cause that occurred in at least 15% of patients. All-grade AEs were substantially lower in the group of patients treated with pembrolizumab monotherapy (26%) than in the groups of patients who received chemotherapy in combination with pembrolizumab (75%) or cetuximab (66%).15 The rate of grade 3 or higher AEs was highest in the group given pembrolizumab plus chemotherapy (47%), followed by 39% in the group given cetuximab plus chemotherapy and 7% for patients given pembrolizumab monotherapy. The most common grade 3 or higher AEs occurring in the pembrolizumab monotherapy group were anemia (5%), fatigue (3%), reduced weight (2%), and hypokalemia (2%). The most common grade 3 or higher AEs in the pembrolizumab plus chemotherapy group were anemia (25%), neutropenia (18%), and reduced neutrophil count (11%).

KEYNOTE-012

In KEYNOTE-012, the safety and efficacy of pembrolizumab monotherapy was specifically evaluated in patients with PD-1–positive R/M HNSCC.¹⁹ Of the 104 patients screened, tumors in 81 patients were positive for PD-1; among these patients, 60 received at least 1 dose of pembrolizumab 10 mg/kg. Patients were also divided into subgroups based on human papillomavirus (HPV) status; 23 patients were in the HPV-positive (HPV+) group and 37 patients were in the HPV-negative (HPV-) group. This subgrouping was done to assess whether treatment responses differed according to HPV status.

The primary end points were safety and ORR, defined as the proportion of patients who reached CR or PR as assessed by central review per the RECIST version 1.1 guidelines.¹⁹ All enrolled patients were included in the safety analysis. The most commonly reported AEs of any grade were fatigue (20%), pruritus (12%), and rash (5%). None of the reported grade 3 TEAEs occurred at markedly higher frequencies than did the others.

Among the 45 patients included in the efficacy analysis, whose responses were assessed via central imaging review, the ORR was obtained for 18% (95% CI, 8%-32%), which included 1 patient who obtained a CR and 7 patients who obtained a PR.¹⁹ The disease progressed in 56% of patients (n = 25). No notable differences were observed in outcomes between the HPV+ and HPV- groups.

These studies show that despite improved outcomes in patients with HNSCC who are treated with nivolumab or pembrolizumab in combination with chemotherapy compared with those given chemotherapy and cetuximab or chemotherapy alone, the durations of response are short and long-term prognosis remains poor, particularly in patients with advanced or R/M HNSCC and in those whose tumors do not overexpress PD-1.^10,11,14,15 Compared with previously standard therapies, the efficacy rates of single-agent PD-1 antibodies are low, regardless of PD-1 CPS.¹⁹ Furthermore, most patients who receive chemotherapy in combination with pembrolizumab will experience AEs that affect QOL. They will also experience higher rates of severe AEs than will patients treated with chemotherapy and cetuximab or chemotherapy alone.¹⁵

FTI THERAPIES

At initial diagnosis, mutated HRAS proto-oncogenes are present in about 4% to 8% of HNSCC tumors at a rate of up to 20% in high-grade histologic subtypes (such as mucoepidermoid carcinoma, adenocarcinoma, and salivary duct carcinoma and have been reported in approximately 15% of cases with cetuximab-resistant HNSCC.^3,5,20-22 This therapeutic gap could be filled with FTI therapies, which inhibit the farnesylation process that is necessary for cellular membrane insertion and protein signaling in HRAS-associated–positive tumors.^3,5

Developing therapeutics that successfully target the Ras-Raf family pathway has challenged researchers since the 1990s.^3,23 Some studies of investigational FTI agents, such as lonafarnib, have yielded disappointing results.^3,23,24 Success was finally achieved in 2021, when tipifarnib became the first FTI therapy to be granted Breakthrough therapy designation (BTD) by the FDA for the treatment of patients with R/M HRAS-mutant HNSCC with a variant allele frequency (VAF) of at least 20% after disease progression on platinum-based chemotherapy.²⁵

Lonafarnib

Lonafarnib was developed as a novel tricyclic nonpeptidomimetic compound to inhibit FTase.²⁴ Thirty-two patients with advanced, treatment-naive HNSCC were treated with lonafarnib as an induction treatment during a 4-arm, phase 1b study; results showed clinical responses at all dose levels (100, 200, or 300 mg twice daily for 8 -14 days before surgical resection). Of the 22 evaluable patients, 4 experienced marked tumor reduction.

Based on these results, a 2-stage, open-label, phase 2 study was launched to characterize the efficacy and safety of lonafarnib treatment (at the maximum-tolerated dose of 200 mg) in patients with R/M HNSCC after failure of platinum-based chemotherapy.²⁴ Fifteen patients were enrolled from October 2003 to May 2004. The primary end point was ORR, defined as complete or partial response according to modified World Health Organization criteria. Secondary end points included PFS, clinical benefit (defined as response or stable disease for ≥ 3 cycles of treatment), safety, and tolerability.

No objective responses were reported in this study.²⁴ Less than half of the participants (47%) had stable disease for greater than 3 cycles of treatment over the course of more than 12 weeks. All patients experienced disease progression; both median PFS and median time to progression were 2.04 months (95% CI, 0.92-4.01).

None of the 14 patients who were evaluable for safety and tolerability died from a TEAE.24 Most TEAEs were grade 1 or 2, the most common being diarrhea (71%), nausea (64%), and fatigue (57%). One patient experienced a grade 4 TEAE, which was hyperuricemia. One patient each experienced a grade 3 TEAE of anorexia, corrected QT interval prolongation, infection without neutropenia, cardiac ischemia, or syncope.

These results indicated that although lonafarnib therapy was safe and tolerable, it was not efficacious.²⁴ Consequently, this phase 2 study was closed to further accrual, and no further studies involving lonafarnib were planned.

Tipifarnib

Tipifarnib is a first-in-class nonpeptidomimetic quinolinone that binds and potently inhibits FTase (half minimal inhibitory concentration of 0.86 nM for lamin B farnesylation).¹⁶ As reported by Gilardi et al, tipifarnib inhibits HRAS farnesylation, displaces it from cellular membranes, and inhibits angiogenesis and vasculogenesis. Tipifarnib also induces differentiation in patient-derived tumors, is selectively cytotoxic to HRAS-mutant HNSCC in vitro, and is highly active in HRAS-mutant HNSCC xenografts; its activity in HRAS-mutant HNSCC is not dependent on genotype.³

In more than 70 clinical trials that were conducted from the late 1990s through the early 2000s, tipifarnib was extensively studied in a variety of tumor types.³ During this time, no methods existed (ie, NGS) to identify patients with specific driver mutations. Therefore, it was not possible to screen patients for the presence ofmutant HRAS in tumors, which could have helped to identify those most likely to benefit from tipifarnib treatment.

Studies of tipifarnib resumed in 2015, this time with the benefit of new methods to enrich clinical activity.^3,16 RUN-HN (NCT02383927) was a phase 2, open-label, single-arm, multicenter, international study. Patients with R/M HRAS-mutant HNSCC (N = 30) were treated with tipifarnib; a summary of key efficacy and safety data of RUN-HN and current FDA-approved therapies are presented in Table 1.^13-16 Safety was evaluated in all patients, but efficacy studies were limited to patients with tumors with HRAS-mutant VAF of at least 20% (N = 22); this is considered a high level of VAF. Two of these patients were nonevaluable, because 1 withdrew consent, and the other discontinued because of symptomatic deterioration prior to efficacy evaluation.¹⁴

The median age of enrolled patients was 63 years (range, 20-89); 68.2% were men, and the median number of prior therapies was 2 (range, 0-6). Of the patients who received previous treatments, 20 received platinum therapy, 14 received immunotherapy, and 11 received cetuximab.¹⁶ The primary end point of the study was investigator-assessed ORR, and secondary end points included safety and tolerability. Exploratory end points included PFS and OS.

Among the efficacy-evaluable patients, the ORR was 55% (95% CI, 31.5%-76.9%); PFS was 5.6 months (95% CI, 3.6-16.4), and OS was 15.4 months (95% CI, 7-29.7).¹⁶ All patients with a high HRAS-mutant VAF received clinical benefit from tipifarnib; 11 patients obtained a PR, and 9 patients obtained stable disease.

This study reported grade 3 or higher TEAEs that occurred in at least 10% of all patients. Fifteen patients (50%) experienced blood and lymphatic system disorders, the most common of which were anemia, which occurred in 11 patients (37%), and lymphopenia, which occurred in 4 patients (13%). Nine patients (30%) experienced metabolism and nutrition disorders and 9 patients (30%) experienced respiratory, thoracic, or mediastinal disorders. Grade 3 or higher gastrointestinal disorders occurred in 6 patients (20%); 3 patients (10%) experienced nausea.

As mentioned previously, mutated HRAS proto-oncogenes are present in about 4% to 8% of HNSCC tumors.^5,20 Although the study population was small, RUN-HN provided evidence in support of the role of mutated HRASas an oncogenic driver of certain HNSCC tumors and the ability of tipifarnib to target such tumors.¹⁶ These results ultimately led to tipifarnib receiving BDT status from the FDA and provided the impetus for further investigations in biomarker-selected cohorts of patients with HNSCC.^16,25

AIM-HN/SEQ-HN (NCT03719690) is an international, multicenter, open-label, 2-cohort, noncomparative study of tipifarnib in adult patients with HRAS -mutant HNSCC. To date, recruitment is ongoing.^26,27 Key inclusion criteria include histologically confirmed HNSCC that is not amenable to local therapy with curative intent; documentation of treatment from the most recent prior therapy (≥ 1 platinum-containing regimen, known tumor missense HRAS mutation, and VAF value), measurable disease according to RECIST version 1.1, and ECOG of 0 to 1. Key factors for study exclusion include salivary gland or thyroid primary cutaneous squamous or nonsquamous histologies.

Patients will orally receive 600 mg of tipifarnib twice daily, on days 1 through 7 and 15 through 21 over the course of 28-day treatment cycles.^26,27 The primary outcome measures are ORR in patients with mutated HRAS, as defined by the RECIST version 1.1 guidelines and determined by independent review. Secondary outcomes include the total time to response, duration of response, time to progression, PFS, 1-year PFS, 1-year OS, safety and tolerability, and pharmacokinetics in patients with HRAS-mutant HNSCC.

On July 6, 2021, Kura Oncology, Inc, announced that it will partner with Novartis in the KURRENT phase 1/2, biomarker-defined clinical trial to evaluate a combination regimen of tipifarnib and alpelisib in patients with HNSCC whose tumors show HRAS overexpression or PI3KCαmutation and/or amplification.²⁸ Alpelisib is an orally administered PI3K inhibitor that is currently indicated in combination with fulvestrant for the treatment of postmenopausal women and men with hormone receptor–positive, HER2-negative, PI3KCα-mutated, advanced or metastatic breast cancer, as detected by an FDA-approved test following progression on or after an endocrine-based regimen.²⁹ This combination therapy trial is based on preclinical data that suggest HRAS and PI3Kα pathways are codependent and involved in developing and maintaining HNSCC in certain patients.²⁸ The KURRENT trial will assess the safety, determine the recommended combination dosing, and measure early antitumor activity of tipifarnib and alpelisib. Trial initiation is expected later in 2021.

CLINICAL DEVELOPMENT OF NEW THERAPEUTICS FOR HNSCC

As the genomic landscape of HNSCC continues to evolve and become better defined, more novel targeted agents have been developed and are being investigated as potential treatments for HNSCC. Table 2 provides a summary of some the investigational agents and their associated trials that were discussed at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.^30-35 Two of these agents, camrelizumab and toripalimab, are PD-1 checkpoint inhibitors being tested in phase 3 clinical trials.^36,37

CAPTAIN-1st (NCT03707509) was a randomized, double-blind, placebo-controlled, multicenter, China-based, phase 3 trial that assessed camrelizumab combined with gemcitabine and cisplatin in adult patients with treatment-naive R/M nasopharyngeal carcinoma.³⁶ The primary end point was PFS. Among the 134 patients in the camrelizumab group, the median PFS was 9.7 months (95% CI, 8.3-11.4) compared with 6.9 months (95% CI, 5.9-7.3) in the placebo group. Disease progression or death occurred in 49% of patients in the camrelizumab group compared with 64% of patients in the placebo group at the time of interim analysis.

Nearly all patients in both groups in the CAPTAIN-1st trial experienced grade 3 or higher AEs; the most common of camrelizumab-associated AEs were reduced white blood cell count (66%), reduced neutrophil count (64%), and reduced platelet count (40%).³⁶ Ten AE-related deaths (7%) were reported in the camrelizumab group compared with 7 (5%) in the placebo group, and rates of discontinuation due to AEs were higher in the camrelizumab group (10%) in comparison with the placebo group (5%).

At the 2021 ASCO Annual Meeting, Xu et al presented the results of JUPITER-02 (NCT03581786), a randomized, double-blind, placebo-controlled, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as a first-line treatment for R/M nasopharyngeal carcinoma.³⁷ The primary end point was PFS in the intention-to-treat population. The median PFS of patients in the toripalimab group was 11.7 months versus 8 months for patients in the placebo group (HR, 0.52; 95% CI, 0.36-0.74). The 1-year PFS was 49% in the toripalimab group versus 28% in the placebo group. Most patients in both groups experienced grade 3 or higher AEs at similar rates; however, immune-related AEs of all grades were higher in patients treated with toripalimab (39.7%) compared with patients who received placebo (18.9%).

Targeted therapeutics that are already FDA-approved as cancer treatments are also being studied for potential HNSCC indications as monotherapies and/or in combination with chemotherapy or other HNSCC-approved drugs. Among these are bevacizumab, a VEGF inhibitor; cabozantinib, an inhibitor of c-Met, VEGFR2, AXL, and RET; and ipilimumab, a CTLA4 monoclonal antibody.³⁸

FUTURE DIRECTIONS FOR HNSCC SOLID TUMOR TREATMENT

As explained by Malone and Siu, the goal of genomic sequencing studies within precision medicine is to find data that can be applied in patient care settings to aid prognostication, inform therapeutic decision-making, and identify actionable biomarkers for which novel therapeutic agents can be developed.⁵ As demonstrated by the recent success of early trials of tipifarnib, new targeted agents can provide patients with HNSCC the opportunity to receive personalized treatment based on the specific molecular alterations and cellular features of their tumors, potentially leading to improved outcomes and prognoses for this previously difficult-to-treat population.^5,16

However, it is also important to note that tumors are adept at developing resistance to targeted regimens.^5,39 To overcome this therapeutic challenge, multiple strategies to circumvent resistance mechanisms and/or delay their development will need to be deployed. These strategies include the use of combination regimens that are informed by reliable models of clinical efficacy; dynamic monitoring of the changing molecular landscape of HNSCC to discover resistant clones before the progression of disease; and the establishment of relevant preclinical models of HNSCC that reflect the disease at the genetic, histological, and functional levels so that the molecular modifiers of responses to therapies used in clinical practice or studied in clinical trials can be better understood.³⁹

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