Concomitant administration of motolimod with cetuximab (Erbitux) increases the innate and adaptive immune response in the blood and the tumor microenvironment in head and neck squamous cell carcinoma (HNSCC), overcoming negative prognostic biomarkers of cetuximab therapy alone, according to the biomarker data from a recent phase Ib clinical trial that was presented at the 2016 Head and Neck Cancer Symposium. The trial was recently amended to add nivolumab to the combination of cetuximab and motolimod.

“We know that PD-1 and PD-L1 are overexpressed in head and neck cancer, and so it was somewhat irresistible to combine our baseline treatment of cetuximab and motolimod with the PD-L1 inhibition pathway. EGFR itself drives PD-L1, so combining cetuximab with anti-PD-1 inhibitor makes sense. So, we’ve amended this trial. We’re now accruing to treatment with cetuximab, motolimod, and the anti—PD-L1 nivolumab in this trial,” said lead author Robert Ferris, MD, PhD, professor, Departments of Otolaryngology, Radiation Oncology, and Immunology, Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

According to the authors of the phase Ib data presented at the symposium, the rationale for combining cetuximab with motolimod (VTX2337) as neoadjuvant therapy was that cetuximab induces cellular immunity that correlates with neoadjuvant clinical response. The phase I dose-escalation and safety of the combination had been established (NCT 01334177).

This study of neoadjuvant cetuximab and motolimod had accrued 14 patients with HNSCC that was stage II-IV, resectable, and located in the oropharynx, oral cavity, hypopharynx, or larynx. These patients were biopsied, treated with cetuximab and motolimod for 4 weeks, and then underwent surgery. The endpoints of the trial were the modulation of immune biomarkers.

Interferon-inducible cytokine IP-10 increased after the patients were administered neoadjuvant cetuximab and motolimod (

 = .0001). After the neoadjuvant treatment, the peripheral blood lymphocytes had an increased frequency of EGFR-specific CD8 T cells. After the neoadjuvant treatment, regulatory T cells had decreased suppressive receptors and transforming growth factor-β, which induces Foxp3. Also, after the neoadjuvant treatment, circulating MDSCs had decreased PD-L1 (

 <.07) and macrophages had increased CD16 expression (

After the neoadjuvant treatment with cetuximab and motolimod, genotyping of T-cell receptors showed increased clonality in peripheral blood lymphocytes (P = .003 by Wilcox signed rank test) and tumor-infiltrating lymphocytes (P = .081 by Wilcox signed rank test). Most patients are more oligoclonal than healthy individuals, and some are very clonal with highly prominent expanded clones. Genotyping of T-cell receptors found that clonality was increased by the combination of cetuximab and motolimod compared with treatment with cetuximab alone.

Recent studies have indicated that the PD-1/PD-L1 pathway is upregulated in the HNSCC microenvironment, and that EGFR blockade prevents interferon-γ-mediated upregulation of PD-L1. Thus, this study has been amended to add nivolumab to the adjuvant treatment with cetuximab and motolimod. The endpoints are still the modulation of immune biomarkers.

The aim is to target the tumor microenvironment, such that tumor immune escape is reversed and T cells eliminate HNSCC. Antitumor T cells are reprogrammed to reverse inhibitory signals. Combining the toll-like receptor agonist, motolimod, with cetuximab and with PD-1 pathway inhibitors, such as nivolumab, may enhance the priming and activity of T cells.

“Targeting the tumor microenvironment requires understanding as well as reversal of immune escape mechanisms in the cellular compartment. Reprogramming antitumor T cells to reverse inhibitory signals can be done by directly disrupting those inhibitory signals, the so-called checkpoint receptor field, and can be done potentially by combining proinflammatory signals, such as toll-like receptor agonists, to chemo-attract cells into the microenvironment and to create good inflammation to overcome suppressive factors,” said Ferris.

Recent findings have shown tremendous promise for nivolumab in head and neck cancer. Bristol-Myers Squibb (BMS) announced in January 2016 that nivolumab improved overall survival versus investigator’s choice of therapy for patients with platinum-refractory squamous cell carcinoma of the head and neck in the phase III CheckMate-141 trial. Findings from the study are being discussed with the FDA and other health authorities, according to BMS.

	Ferris RL, Kansy BA, Gibson SP, et al. A phase 1b study of neoadjuvant immune biomarker modulation with cetuximab and motolimod in head and neck cancer (HNC). Presented at: 2016 Multidisciplinary Head and Neck Cancer Symposium; Feb 18-20; Scottsdale, AZ. Abstract 8.

View more from the 2016 Multidisciplinary Head and Neck Cancer Symposium

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An early-stage trial is examining the addition of nivolumab to a cetuximab regimen in head and neck squamous cell carcinoma. 

Immunotherapy Continues to Advance in Head and Neck Cancer

Among patients with HPV-negative, locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC) with a poor prognosis, adding cetuximab (Erbitux) to induction chemotherapy and hyperfractionated or accelerated chemoradiation therapy (CRT) produced long-term control, according to results from a phase II trial.

The randomized study, which was presented at the 2016 Head and Neck Cancer Symposium, enrolled 110 patients who were diagnosed with LA-HNSCC between September 2006 and April 2010. In 103 of these patients, HPV status was evaluated, and 56 were HPV-negative.

These 56 HPV-negative patients were randomized to 2 treatment arms: 32 patients received Cetux-FHX (concurrent cetuximab, 5-FU, hydroxyurea, and 1.5 Gy twice-daily RT every other week to 75 Gy), and 24 patients received Cetux-PX (cetuximab, cisplatin, and accelerated RT with delayed concomitant boost to 72 Gy in 42 fractions). Both arms received 2 cycles of weekly induction chemotherapy.

Previous phase II trials indicated cetuximab was well tolerated and had high response rates when added to induction chemotherapy, though these trials were not randomized. Research has also previously shown that cetuximab increased survival in the metastatic setting when added to cytotoxic chemotherapy and in the curative-intent setting when added to single-modality radiotherapy.

“The primary objective for this trial was to assess the tolerability and efficacy of adding cetuximab to induction chemotherapy and chemoradiotherapy. A secondary objective with this trial was to compare 2 chemoradiotherapy platforms,” said lead study author James Melotek, MD, a radiation oncology resident at the University of Chicago.

Overall survival (OS) at 5 years for the entire cohort was 80.3% (95% CI, 73.1%-88.3%) and for the HPV-negative subset was 72.5% (95% CI, 61.6%-85.4%). Progression-free survival (PFS) at 5 years was 74.1% (95% CI, 66.3%-82.9%) for the entire cohort and 65.9% (95% CI 54.6%-79.6%) for the HPV-negative group.

No significant difference was found in OS (

 = .57) between the two HPV-negative treatment arms. Five-year OS was 71.4% (95% CI, 57.1%-89.1%) for the Cetux-FHX arm and 74.2% (95% CI, 58.4%-94.3%) for the Cetux-PX arm. Median follow-up was 68 months.

PFS at 5 years was 62.1% (95% CI, 47.2%-81.6%) for the Cetux-FHX arm and 70.8% (95% CI, 54.8%-91.6%) for the Cetux-PX arm. Late outcomes in the HPV-negative subset at 5 years were locoregional failure in 26.9% (95% CI, 16.0%-39%) and distant failure in 7.2% (95% CI, 2.3%-16%).

Neither OS nor PFS were affected by tobacco use, alcohol use, or HPV status. For both OS and PFS, however, age was a significant predictor (HR, 1.07; 95% CI, 1.02-1.12; 

Patient demographics were comparable between the 2 arms. Median age was 57 years (range, 32-81 years). Most of the patients (84%) were male. Almost all (98%) patients had stage IV carcinomas (61% ≥T3, 77% ≥N2b, 54% T4 or N3). The majority (66%) of patients smoked ≥10 packs per year.

The induction chemotherapy had an overall response rate of 91%. Severe toxicity during induction chemotherapy was limited to rash and myelosuppression. Rash grade ≥3 occurred in 23% of patients, and neutropenia ≥3 occurred in 38% of patients.

Each arm had distinct adverse events (AEs) with CRT. The Cetux-FXH arm had increased dermatitis, with grade ≥3 dermatitis in 81% of patients versus 51% in the Cetux-PX arm (P <.01). The Cetux-PX arm had increased myelosuppression, with grade ≥3 neutropenia in 38% of patients versus 18% in the Cetux-FHX arm (P = .018), and increased dehydration, with grade ≥3 dehydration in 17% of patients versus 2% in the Cetux-FHX arm (P <.01). One death (sepsis) occurred on the Cetux-PX arm.

“In conclusion, the addition of cetuximab to induction chemotherapy and chemoradiotherapy in this trial was tolerable and produced long-term control of locally advanced head and neck cancer, particularly among poor-prognosis, HPV-negative patients. Both chemoradiotherapy platforms were well tolerated without any significant differences in survival,” said Melotek.

He suggested that additional investigation of cetuximab might be merited in the neoadjuvant setting with intensification of treatment in high-risk subgroups and in the concurrent setting with nonplatinum-based CRT.

	Melotek JM, Haraf DJ, Blair EA, et al. Final results of a randomized phase 2 trial investigating the addition of cetuximab to induction chemotherapy and accelerated or hyperfractionated chemoradiation therapy for locoregionally advanced head and neck cancer: HPV-negative subset analysis. Presented at: 2016 Multidisciplinary Head and Neck Cancer Symposium; Feb 18-20, 2016; Scottsdale, AZ. Abstract 7.

Among patients with HPV-negative, locoregionally advanced head and neck squamous cell carcinoma with a poor prognosis, adding cetuximab (Erbitux) to induction chemotherapy and hyperfractionated or accelerated chemoradiation therapy produced long-term control.

Cetuximab Improves Long-Term Control in HPV-Negative Head and Neck Cancer

In patients treated with definitive radiation therapy (RT) for HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), most recurrences can be detected via imaging at 3 months and physical examinations during the first 6 months after treatment, according to research presented at the 2016 Multidisciplinary Head and Neck Cancer Symposium.

Most recurrences and toxicities were detected by posttreatment imaging at 3 months and physical examinations during the 6 months after treatment. Patients experienced low rates of permanent toxicity, potentially because a multidisciplinary team delivered treatment. Minimizing posttreatment tests without compromising outcomes might reduce patient stress and financial burden.

Previous retrospective and prospective studies have shown that while HPV-associated cases of OPSCC are increasing in frequency, treatments result in decreased toxicities and increased survival. As the number of patients with HPV-positive oropharyngeal cancer and the number of survivors grows, best follow-up care practices need to consider typical time to recurrence and the most effective methods for recurrence detection.

“The purpose of our study is really to determine when these patients fail and also when they have side effects so we know how to guide our optimal follow-up schedule. If you look at the NCCN guidelines, it’s a one-size-fits-all. So whether you’re HPV-associated or not associated, the follow-up recommendations are the same,” said lead study author Jessica Frakes, MD, an assistant professor in the department of Radiation Oncology at the H. Lee Moffitt Cancer Center and Research Institute, during a presscast.

This study examined data from 245 patients diagnosed with either HPV-positive or p16-positive OPSCC. These patients all received definitive RT, and most patients (85%) also received concurrent chemotherapy.

Median follow-up was 36 months. Every patient received a 3-month posttreatment PET/CT scan. Every patient also received physical examinations every 3 months in the first year after treatment, every 4 months in the second year, every 6 months in years 3 to 5, and then annually. Local control was achieved in 239 of 245 patients (98%).

“As you can see from our results here, they’re excellent. Our local control was 98% at 3 years,” said Frakes.

Six local failures were all detected by physical examination via either direct visualization (n = 2) or flexible laryngoscopy (n = 4). Regional failures in the neck (n = 9) were largely detected (89%) by posttreatment imaging. Patients who suffered regional failure were more likely to have had ≥5 nodes or the presence of level 4 lymph nodes upon initial diagnosis and treatment. By 3 years, regional control maintained in 95.3% of patients.

Of distant metastases (n = 21), 71% (n = 15) were discovered by patient symptoms or 3-month posttreatment imaging. An increased risk of distant metastases occurred in patients with lymph nodes >6 cm in diameter, bilateral lymph node carcinomas, ≥5 nodes, or level 4 nodes upon initial diagnosis and treatment. For all patients, 3-year overall survival was 91%.

Late toxicity of grade ≥3 occurred initially in 9% of patients. Late toxicity was defined as side effects that occurred 3 months posttreatment or later. These severe late effects included 19 grade 3 toxicities and 2 grade 4 toxicities with the majority (76%; 16 /21) resolved at the time of last follow-up. Since most cases of late toxicity were resolved, the overall toxicity rate was 2%.

“In conclusion, what we gathered from our study was that the majority of the recurrences and toxicities can be detected by posttreatment imaging at 3 months and physical examinations during that first 6 months following treatment. Regardless of those patients who are at higher risk for regional or distant failures, they still had that same time course of toxicity and/or recurrence,” explained Frakes.

Frakes suggested that excessive posttreatment surveillance and imaging could increase anxiety and financial burden to the patients. These results indicated that no further imaging is warranted if posttreatment PET/CT scans are negative.

“Minimizing these tests that do not compromise outcomes [might] help decrease patient anxiety and stress as well as the financial burden for our patients. And lastly, our outcomes are excellent with lower rates of permanent toxicity, and we think this is partly due to the fact that they are treated with specialized, multidisciplinary teams,” concluded Frakes.

	Frakes JM, Naghavi AO, Strom T, et al. Detection of recurrence in HPV associated oropharynx squamous cell carcinoma. Presented at: 2016 Multidisciplinary Head and Neck Cancer Symposium; February 18-20, 2016; Scottsdale, AZ. Abstract 6.

In patients treated with definitive radiation therapy for HPV-positive oropharyngeal squamous cell carcinoma, most recurrences can be detected via imaging at 3 months and physical examinations during the first 6 months after treatment.

Megan Garlapow, PhD

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Immunotherapy Continues to Advance in Head and Neck Cancer

Cetuximab Improves Long-Term Control in HPV-Negative Head and Neck Cancer

HPV+ Oropharyngeal Cancer Recurrence Typically Detected Within 6 Months of Treatment