Vijay Patil, MBBS, MD, DM
IN PATIENTS with locally advanced squamous cell carcinoma of the head and neck, nimotuzumab—a humanized monoclonal antibody against the epidermal growth factor receptor—in combination with cisplatin and radiotherapy was superior to cisplatin and radiotherapy alone in improving progression-free survival, disease-free survival, and locoregional tumor control, according to research conducted by Vijay Patil, MBBS, MD, DM, of the Tata Memorial Center in Mumbai, India, and colleagues.
Mark Agulnik, MD
These results were originally presented at the 2018 ASCO Annual Meeting and were discussed at the Best of ASCO Chicago by Mark Agulnik, MD, Professor of Hematology and Oncology at Northwestern University Feinberg School of Medicine in Chicago, along with this year’s other top selected abstracts in head and neck cancer.1,2
The median duration of progression-free survival in patients who received nimotuzumab was significantly longer compared with chemoradiation therapy alone: 60.3 months vs 21.0 months. The 2-year progression-free survival rate was also significantly improved with nimotuzumab: 58.9% vs 49.5% (P = .022).
This was the first phase III trial of nimotuzumab. According to the investigators, “this combination provides a new therapeutic option in the armamentarium against locally advanced squamous head and neck cancer.”
Study Design
THE SINGLE-INSTITUTION phase III randomized study was conducted in 536 patients with locally advanced stage III or IV squamous head and neck cancer who were treated with weekly nimotuzumab in addition to radiation and cisplatin chemotherapy or chemoradiation therapy alone. Patients were equally allocated to receive either radical radiotherapy (66–70 Gy) with weekly cisplatin (30 mg/m2) or the same schedule of chemoradiation therapy along with weekly nimotuzumab (200 mg).
Patients in the trial were all 18 years or older, had a Karnofsky performance status of at least 70, and had adequate organ function; the median follow-up was 33.0 months. The primary endpoint was progression-free survival, and key secondary endpoints were disease-free survival, duration of locoregional tumor control, and overall survival.
“This combination [nimotuzumab plus chemoradiation] provides a new therapeutic option in the armamentarium against locally advanced squamous head and neck cancer.”— Vijay Patil, MBBS, MD, DM
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Improvement in Outcomes
COMPARED WITH chemoradiation therapy alone, 2-year disease-free survival was higher with nimotuzumab (59.2% vs 49.0%; P = .030), and 2-year locoregional control was also significantly better with the addition of nimotuzumab (65.1% vs 56.5%; P = .021).
“The addition of nimotuzumab decreased the hazard ratio of disease recurrence by a quarter,” said Dr. Agulnik. “And when we look at locoregional control, the increment in progression-free survival seen with the addition of nimotuzumab is largely contributed to the decrease in locoregional failures.”
There was also a trend toward improvement in overall survival with the addition of nimotuzumab: 43.4 months vs 31.3 months (P = .222). The hazard ratio in favor of nimotuzumab was 0.851, suggesting a 15% reduction in the risk of death, but this was not statistically significant.
Grade 3 to 5 adverse events were similar between the two arms. However, patients in the nimotuzumab arm experienced a higher incidence of mucositis (66.7% vs 55.8%; P = .010).
Dr. Agulnik’s Take on the Research
“CHEMORADIATION IS a common treatment strategy, but it certainly needs [the addition of other strategies] to improve outcomes,” he said. “We’ve looked at neoadjuvant and adjuvant strategies, we’ve looked at altering radiation schedules, and we’ve looked at the addition of second chemotherapeutic agents to cisplatin. Most of them, however, have failed to improve outcomes.”
NIMOTUZUMAB
- Nimotuzumab is a humanized monoclonal antibody that targets the extracellular region of the epidermal growth factor receptor with high specificity, thereby blocking ligand binding and receptor activation.
- In the United States, nimotuzumab has had Orphan Drug status for glioma since 2014.
- The drug is being studied in clinical trials for a variety of other cancers, including esophageal cancer, nasopharyngeal cancer, non–small cell lung cancer, gastric cancer, and colorectal cancer.
“What’s impressive is that this study was randomized. It was done in a single institute, but a very good single institute,” he said. “The delivery of radiation and cisplatin was excellent and well balanced in the two groups, with a high compliance rate. However, there is a limitation: most people do not use 30 mg/m2 in treatment. Therefore, what is the true relevance to a group that receives a treatment probably not consistent with standards?” Other limitations of the study, he noted, were a low oral cavity population and immature overall survival data.
According to Dr. Agulnik, the cumulative cisplatin dose correlates with the overall survival outcome. Cisplatin at 100 mg/m2 every 3 weeks for two to three doses comes out to 200 to 300 mg/m2, and cisplatin at 40 mg/m2 weekly for 6 to 7 weeks equals a total dose of 240 to 280 mg/m2. “And in this study, at 30 mg/m2, we’re dosing below that at 180 to 210 mg/m2,” he said. “So, the inferior dosing of the drug probably has an impact here.” However, 200 mg/m2 is considered an adequate dose of cisplatin, and nearly 80% of patients in both arms had received it, which is slightly better than the RTOG 0522 study.3
Prior research has established that the addition of cetuximab to radiation and cisplatin did not improve outcomes.3 “So, the question is, what makes this study different?” he asked. “Compared to the RTOG 0522 trial, this trial had more [human papillomavirus]– negative patients, more hypopharynx patients, and more T3 to T4 patients. Patients also received fewer radiation interruptions and a little bit more cisplatin as well, despite a weekly dose of 30 mg/m2.”
Chemoradiation with concurrent cisplatin (100 mg/m2 every 3 weeks) remains the gold standard of care in locally advanced squamous cell carcinoma of the head and neck. The addition of nimotuzumab, however, needs to be considered when weekly radiosensitization is planned. ■
DISCLOSURE: Drs. Patil and Agulnik reported no conflicts of interest.
REFERENCES
1. Patil VM, Noronha V, Joshi A, et al: Results of a randomized phase III study of nimotuzumab in combination with concurrent radiotherapy and cisplatin versus radiotherapy and cisplatin alone, in locally advanced squamous cell carcinoma of the head and neck. 2018 ASCO Annual Meeting. Abstract 6000. Presented June 3, 2018.
2. Agulnik M: Head and neck cancer. 2018 Best of ASCO Chicago. Special session. Presented August 11, 2018.
3. Ang KK, Zhang Q, Rosenthal DI, et al: Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab or stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 32:2940-2950, 2014.
