NEW YORK CITY—Head and neck squamous cell carcinoma (HNSCC) is relatively uncommon in the U.S., accounting for approximately 4 percent of all cancer in the country, and it continues to be a challenging area of treatment for oncologists, especially with the rise of HPV-associated disease.
“Development of effective therapies for metastatic HNSCC has been challenging and progress has been slow,” according to Charu Aggarwal, MD, MPH, Assistant Professor of Medicine, Hospital of the University of Pennsylvania, Philadelphia, who discussed the treatment of this disease during a presentation at the Chemotherapy Foundation Symposium, held Nov. 8-10.
Role of PD-1 Inhibitors
The hurdles faced by oncologists working with this patient population can be seen in the history of FDA approvals. Prior to 2016, the last drug approved for metastatic disease was cetuximab in 2006. However, an uptick in treatment options has been seen in the last year with the approval of pembrolizumab as well as nivolumab.
“A few years ago, approval for PD-1 inhibitors came about for other diseases, like melanoma and lung cancer, and provided a very interesting and exciting opportunity for the treatment of metastatic HNSCC with the use of nivolumab and pembrolizumab in several clinical trials,” Aggarwal noted.
Pembrolizumab received FDA approval in August 2016 for patients with recurrent or metastatic HNSCC that continued to progress despite standard-of-care treatment with chemotherapy. The FDA granted accelerated approval based on early data from 174 patients with HNSCC enrolled in the nonrandomized KEYNOTE-012 trial. Twenty-eight patients (16%) experienced a tumor response following treatment with pembrolizumab. In 23 (82%) of those patients, the tumor response lasted for 6 months or longer, and several have lasted for more than 2 years, according to the FDA.
In November 2016, the second immunotherapy drug, nivolumab, was approved for patients who have progressed during chemotherapy with a platinum-based drug for cancer that has recurred or metastasized after platinum-based chemotherapy.
“Checkmate 141 was a large, randomized, phase III trial evaluating the use of nivolumab in the treatment of patients with metastatic, recurrent disease that had previously had platinum-based doublet chemotherapy,” Aggarwal explained. “Patients received either cetuximab, methotrexate, or docetaxel versus nivolumab and were randomized 2:1 with a primary endpoint of overall survival (OS).”
The trial, which is the basis of the FDA approval, demonstrated a statistically significant and clinically meaningful improvement in OS associated with the nivolumab arm (HR 0.7 [95% CI: 0.52, 0.92]; p=0.0101, stratified log-rank test). Estimated median OS was 7.5 months (95% CI=5.5, 9.1) in the nivolumab arm and 5.1 months (95% CI=4, 6.0) for investigator's choice (N Engl J Med 2016;375(19):1856-1867).
Aggarwal noted that several updated analyses of this data were presented at the 2017 ASCO Annual Meeting. One such analysis looked more at patients treated in the first-line (J Clin Oncol 2017; doi: 10.1200/JCO.2017.35.15_suppl.6019). “Out of the entire population, they looked at about 78 patients that received nivolumab in the first-line setting and, again, OS was significantly improved compared to standard of care chemotherapy,” she said.
Additional studies have also continued the analysis of pembrolizumab. In the phase II, KEYNOTE-55 trial, pembrolizumab was dosed at 200 mg at a flat rate, according to Aggarwal. “This study specifically included patients who were resistant to both platinum and cetuximab, and overall survival rate was very similar to the response rate seen in the nivolumab study, approximately 16-18 percent.”
At the ESMO 2017 Congress, the phase III KEYNOTE-40 was presented, which compared pembrolizumab to standard-of-care chemotherapy. “Even though pembrolizumab was numerically associated with a higher survival compared to chemotherapy, it didn't quite meet statistical significance,” Aggarwal noted. “The median OS was 8.4 months, which again, was very similar to what had been seen on the nivolumab trial.
“So why was this? On this trial, 12 percent of patients receiving chemotherapy went to receive subsequent immune checkpoint inhibitors compared to only 4.5 percent in the pembrolizumab arm,” she continued. “When evaluated separately, patients who received immune checkpoint inhibitors had a survival of 20.1 months compared to 9.8 months in patients who received other subsequent therapies.
“Could this have diluted the picture? If we look at the curves after censoring following the first subsequent immune checkpoint inhibitor, we now find that p value does indeed become statistically significant.”
Given the body of available research, Aggarwal noted that PD-1 inhibitors are now considered standard therapy in the management of HNSCC. Additionally, she pointed out, it is important to note that currently nivolumab is the only agent with phase III data that shows an OS advantage.
Impact of Biomarkers
Do biomarkers have a role in the treatment of HNSCC? According to Aggarwal, there is evidence to support this.
“Head and neck cancer enjoys a favorable place on the mutational landscape,” she said. “We know from other tumors that patients with high tumor mutational burden respond favorably to immunotherapy and this has also been shown in HNSCC.”
According to data presented at the ASCO 2017 Annual Meeting (J Clin Oncol 2017; doi:10.1200/JCO.2017.35.15_suppl.6009). “Mutational load (ML) and gene expression profile (GEP) are independently predictive of response to pembrolizumab in HPV-/EBV- patients with HNSCC; GEP was predictive regardless of viral status. ML and GEP may have utility in characterizing responses to anti PD-1 therapies and novel cancer regimens in HNSCC,” the study authors wrote.
Additionally, Aggarwal noted, “Responses were highest among patients with both high ML and high GEP,” suggesting these biomarkers do have value in the identification of patients who may respond to immunotherapy.
While the approval of pembrolizumab and nivolumab mark a significant milestone in the treatment of HNSCC with immunotherapy and both agents have been associated with positive responses in this often difficult-to-treat patient population, Aggarwal noted the need for evaluation of combination immunotherapy and other approaches that could lead to higher response rates, improved outcomes, and prolonged survival.
“There are several checkpoints in the cancer-immunity cycle that can be harnessed for activity, such as IDO, an enzyme that is present on tumor cells that have been associated with poor outcomes,” Aggarwal said. “It is associated with immune invasion, so upregulation of IDO has been shown to upregulate regulatory T cells as well as inhibit the activity of PD-1 inhibitors. So, when utilizing an IDO inhibitor, it should synergize the PD-1 inhibitors and potentially increase efficacy.”
A recent phase I/II trial suggests this may be the case (ASCO 2017; Abstract 6010). The ECHO-202/KEYNOTE-037 trial used an IDO inhibitor in combination with pembrolizumab. “The results of the HNSCC cohort show an overall response rate of 34 percent,” Aggarwal reported. She noted that the patients had not previously received a PD-1 inhibitor, so perhaps their response was to pembrolizumab. However, she is looking forward to the data being validated in a phase III study.
Research has shown the addition of bevacizumab, an anti-VEGF monoclonal antibody, to chemotherapy has improved outcomes in several solid tumors. In the realm of HNSCC, pemetrexed plus bevacizumab has had promising efficacy in recurrent and metastatic disease (J Clin Oncol 2011;29(9):1140-1145).
A recent trial, E1305, was designed to evaluate the addition of bevacizumab to a platinum doublet in this patient population (ASCO 2017; Abstract 6000). “There is no targeted therapy that has been approved for the treatment of metastatic HNSCC since cetuximab was approved in 2006,” noted Aggarwal.
In this trial, about 400 patients were enrolled and even though progression-free survival was improved there was significant improvement in OS (HR 0.84). “This is not practice-changing and not standard of care at this time, based on these results,” she said.
While treatment options continue to grow for this patient population, Aggarwal emphasized the importance of tailoring treatments for HPV-associated disease.
“One future direction of research includes HPV-associated HNSCC, which is a distinct entity by virtue of it being virally induced,” she said. “Perhaps we need to use other mechanisms because these are tumors that are not traditionally associated with a high tumor mutational burden.
“There are specific vaccine approaches that are being used and we shouldn't forget research on adoptive T-cell therapy with CAR T cells specifically focusing on HPV-positive cancer cells that are underway.”
Catlin Nalley is associate editor.