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Cetuximab Fails Twice vs Cisplatin for HPV-Related Oral Ca

— Cetuximab resulted in more patient deaths across U.S., German studies

Last Updated October 24, 2018
MedpageToday

SAN ANTONIO -- High-dose cisplatin chemotherapy plus radiotherapy (RT) should remain the standard of care for human papillomavirus (HPV)-related oral cancers, according to two randomized trials that found poorer overall survival with cetuximab (Erbitux).

In the RTOG 1016 trial, overall survival (OS) was substantially and significantly better among patients treated with cisplatin plus RT, with 5-year survival estimates of 84.6% versus 77.9% with cetuximab, Andy Trotti, MD, of the Moffitt Cancer Center in Tampa, Florida, reported here at the American Society for Radiation Oncology () meeting.

Action Points

  • Note that these studies were published as abstracts and presented at conferences. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

And a study from the European Society for Medical Oncology () meeting now underway in Munich reported 2-year OS of 97.5% with cisplatin and 89.4% with cetuximab in a similar group of patients, according to Hisham Mehanna, PhD, of the University of Birmingham in the United Kingdom.

Paul Harari, MD, of the University of Wisconsin, ASTRO president and co-investigator in the RTOG 1016 trial, announced these findings at a press briefing Tuesday, noting the two studies showed nearly identical results.

"At the same day on both sides of the Atlantic, we have powerful corroboration from two major trials, one in the U.S. and one in Europe, showing this impact," he said. "[The ESMO study had] the same trial design -- a little bit smaller, a little bit less power than the 1016 trial -- but it showed in all major parameters higher overall survival and local control with platinum radiation in combination versus cetuximab with radiation."

RTOG 1016 Trial

In the study presented at ASTRO, overall survival was significantly worse in the cetuximab arm (HR 1.45, 95% CI 1.03-2.05), as was progression-free survival (HR 1.72, 95% CI 1.29-2.29). The estimated 5-year progression-free survival was 78.4% (95% CI 73.8-83.0) in cisplatin-treated patients and 67.3% (95% CI 62.4-72.2) in cetuximab-treated patients.

After 5 years, the rate of locoregional failure for cisplatin was lower than with cetuximab (9.9% versus 17.3%), as was the rate of distant metastases (8.6% versus 11.7%). Top-line results of the trial were announced in August and the trial was stopped prematurely.

"It was unknown until the NCI press release for this study a few months ago whether platinum with radiation would give a higher overall survival at 5 years than radiation and cetuximab," Harari said. "Based on this study, we now know that to be true and it gives very important information to practitioners around the world. If a patient is able to receive cisplatin with radiation, it is the preferred agent."

As the fastest-rising cancer among young white men, incidence of oropharyngeal squamous cell carcinoma (OPSCC) has nearly doubled in the U.S. from 1988 to 2004. OPSCC is typically treated with combined doses of RT and chemotherapy, and based on the results from preliminary trials released in 2006, many researchers hypothesized that cetuximab may be a viable substitute for cisplatin. Further, guidelines presented at last year's ASTRO meeting recommended that patients who are unfit for high-dose cisplatin receive concurrent cetuximab or carboplatin.

Randall Kimple, MD, PhD, of the University of Wisconsin School of Medicine and Public Health, said this study standardized treatment for a group of patients that previously had little to no randomized data comparing chemotherapies. However, in patients who cannot tolerate cisplatin because of hearing loss or kidney problems, which may be one-fifth of his patients, he said cetuximab could still be a viable treatment option.

"What is the best treatment for them? Should it be cetuximab and radiation, radiation by itself, or another chemotherapy with radiation?" Kimple said. "That's something we don't really know, and the honest truth is we might never have randomized evidence in this group of patients because it's not a huge group, and to run a clinical trial on only 500 patients is challenging."

Moving forward, Kimple said it was important for researchers to understand the mechanisms behind these results in order to design the most effective clinical trials.

This phase III trial randomized 805 patients with advanced locoregional OPSCC from 2011 to 2014. Most patients were men (90%) and were an average age of 58 years. Patients in the cisplatin arm received 100 mg/m2 every 3 weeks and patients in the cetuximab arm received weekly treatments of cetuximab. Both groups received 6 weeks of accelerated RT (70 Gy in six fractions).

European Findings

From 2012 to 2016, this study recruited 334 patients across 32 centers in the U.K., Ireland, and the Netherlands. Most patients were male here as well (80%), with an average age of 57 years. Individuals in this study were administered RT and either cisplatin or cetuximab, and followed up for 2 years.

Along with the worse overall survival among the cetuximab cohort at 2 years (HR 4.99, 95% CI 1.70-14.67, P=0.001), recurrences were more likely in this group (16.1% versus 6% with cisplatin, HR 3.39, 95% CI 1.61-7.19, P=0.0007).

Safety

In the RTOG trial, patients in the cisplatin arm experienced slightly more serious side effects than those treated with cetuximab using traditional toxicity reporting methods (82% versus 77%). Generally, anemia, hearing loss, nausea, vomiting, neutropenia and kidney injury were more common in the cisplatin group and rashes were more common in the cetuximab group. Long-term, severe dysphagia (difficulty swallowing) was more common in cetuximab patients than those receiving cisplatin (6% versus 4%).

However, the RTOG investigators also included a different metric, the T-score, which measures all high-grade events in the group and averages them across the total number of patients, a method they said better captures the toxicity burden. Using T-scores, patients receiving cisplatin reported a 40% higher rate of high-grade events compared to patients who received cetuximab. The authors said quality of life measures will be reported at a later date.

Contrary to the study presented at ASTRO, the European trial did not report significant differences in the cisplatin and cetuximab arms when looking at grade 3 to 5 toxicity (5.37 versus 5.45 events per patient, respectively) or overall events (29.15 versus 30.05). However, there were more episodes of serious adverse events in patients receiving cisplatin, including renal and hematologic problems (162 versus 95 events with cetuximab).

In an attempt to decrease this treatment's toxicity, Harari said studies are underway to investigate the effects of reducing radiotherapy or of substituting immunotherapy for cisplatin. These trials could be reported within the next 1 to 3 years, he said.

"This approach was to determine if we could substitute a drug that might be less toxic for platinum, but that's just one way to go about this," he said. "There are trials that have compared 70 versus 60 Gy, and even though that may seem like a modest reduction, that has the potential to reduce side effects."

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    Elizabeth Hlavinka covers clinical news, features, and investigative pieces for ľֱ. She also produces episodes for the Anamnesis podcast.

Disclosures

The study presented at ASTRO was supported by grants from NRG Oncology, the NCI Community Oncology Research Program (NCORP), the National Cancer Institute (NCI), Imaging and Radiation Oncology Core (IROC), Eli Lilly, and The Oral Cancer Foundation.

The study presented at ESMO was funded by grants from GSK Biologicals, Silence Therapeutics, and Sanofi Pasteur. Dr. Kong reported receiving grants/payment from PUMA and AstraZeneca, Merck, BMS, MDS, and Avvinity Therapeutics Limited. Dr. Robinson has served as a consultant for Leica Biosystems. Dr. Foran has received payment from MSD and Merck. Dr. Moleron reported receiving payment from Bristol-Myers-Squibb and MSD.

Primary Source

American Society for Radiation Oncology

Trotti A, et al “NRG-RTOG 1016: Phase III trial comparing radiation/cetuximab to radiation/cisplatin in HPV-related cancer of the oropharynx” ASTRO 2018; Abstract LBA4.

Secondary Source

European Society for Medical Oncology

Mehanna H, et al “Cetuximab versus cisplatin in patients with HPV-positive, low risk oropharyngeal cancer, receiving radical radiotherapy” ESMO 2018; Abstract LBA9_PR.