Post-Hoc Analysis Shows Overall Impact of Avasopasem in Reducing Burden of Severe Oral Mucositis in Head and Neck Cancer

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Avasopasem manganese (GC4419) provided an overall clinical benefit vs placebo in reducing the burden of severe oral mucositis in patients with locally advanced head and neck cancer, according to a post-hoc generalized pairwise comparison (GPC) analysis of the phase 3 ROMAN trial (NCT03689712) presented at the 2023 European Congress on Head and Neck Oncology.¹

Findings from the GPC analysis showed that there was a 56% probability that a patient treated with avasopasem would have a better outcome than a patient treated with placebo. Additionally, there was a 33% probability that a patient given avasopasem would have a worse outcome than a patient given placebo, translating to a net treatment benefit of 23% (P = .00019)

"We are pleased to present at [the] European Congress on Head and Neck Oncology the results of the phase 3 ROMAN trial, including a net treatment benefit analysis submitted as part of Galera’s new drug application [NDA],” Mel Sorensen, MD, president and chief executive officer of Galera Therapeutics, stated in a press release.² “This analysis is particularly appropriate for severe oral mucositis, where we believe that no single end point fully characterizes the potential impact of [this] on patient quality of life. We believe the results reinforce avasopasem’s first-in-class potential to reduce severe oral mucositis, a common and debilitating effect of radiotherapy in patients with head and neck cancer. As we work with the FDA on the potential to bring avasopasem to US patients, we also look forward to discussions with European regulatory authorities on a path for patients in Europe.”

For patients with locally advanced head and neck cancer, the standard of care (SOC) is intensity-modulated radiation therapy plus cisplatin.1 With this regimen, approximately 70% of patients develop World Health Organization (WHO) grade 3 or 4 severe oral mucositis. Grade 4 oral mucositis occurs in approximately 20% to 25% of patients. The median duration of oral mucositis is 3 to 4 weeks, and the median onset is at approximately 40 Gy.

Patients with WHO grade 3 oral mucositis have ulcers and require a liquid diet. Those with WHO grade 4 oral mucositis also have ulcers and are unable to tolerate a solid or liquid diet, requiring intravenous or tube feeding.

No drugs are currently approved for the treatment of oral mucositis. However, in February 2023, the FDA granted priority review to avasopasem as a potential treatment for radiotherapy-induced severe oral mucositis in patients with head and neck cancer undergoing SOC treatment.3 The NDA for the drug was supported by data from the phase 2b GT-201 (NCT02508389) and phase 3 ROMAN trials.

ROMAN enrolled patients with locally advanced head and neck cancer who were randomly assigned to receive 90 mg of avasopasem (n = 241) or placebo (n = 166) once per day.¹

Previously reported results from ROMAN showed that patients treated with avasopasem experienced a 16% reduction in the incidence of severe oral mucositis (54% for avasopasem vs 64% for placebo; P = .045). The median duration of severe oral mucositis was 8 days for the avasopasem arm vs 18 days for the placebo arm, translating to a 56% reduction in duration (P = .002). In the avasopasem arm, 24% of patients experienced grade 3 severe oral mucositis compared with 33% in the placebo arm, translating to a 27% reduction in the incidence of grade 4 severe oral mucositis (P = .052). Additionally, the median number of days to first severe oral mucositis was 49 days in the avasopasem group vs 38 days in the placebo group, translating to a 29% delay in first onset (P = .002).

Adverse effect profiles were similar between avasopasem and placebo; however, acute/chronic kidney injury was reduced with avasopasem (10% vs 20% for placebo at 1 year; P = .0043).

Tumor outcomes were also maintained at 1 year for avasopasem vs placebo.

In the GPC review, investigators conducted a simultaneous analysis of several outcomes, prioritized by importance. Pairs were formed with 1 patient from the avasopasem group and 1 patient from the placebo group. For each pair, prioritized outcomes were compared to find which patient had a better outcome. All comparisons were compiled in a summary measure to estimate the net treatment benefit, which was defined as the probability that a patient treated with avasopasem would have a better outcome than a patient treated with placebo.

The outcomes evaluated, in order of priority, included:

• Incidence of WHO grade 4 severe oral mucositis;
• Incidence of WHO grade 3 or 4 severe oral mucositis;
• Number of days of severe oral mucositis through intensity-modulated radiation therapy; and
• Number of days to onset of severe oral mucositis.

When evaluating days of severe oral mucositis and days to onset, a difference of at least 7 days was defined as clinically relevant. For the GPC, patients were stratified by cisplatin schedule (weekly vs every 3 weeks) and treatment setting (post operative vs definitive radiotherapy).

Regarding incidence of grade 4 severe oral mucositis, 28% of pairs were favorable to avasopasem and 15% were favorable to placebo, leading to a 13% net treatment benefit. For incidence of grade 3 severe oral mucositis, 14% and 10% of pairs were favorable to avasopasem and placebo, respectively, translating to a 4% net treatment benefit.

Nine percent and 6% of pairs were favorable to avasopasem and placebo, respectively, for number of days of severe oral mucositis, translating to a 3% net treatment benefit. For number of days to onset of severe oral mucositis, 5% of pairs were favorable to avasopasem vs 2% for placebo, translating to a 3% net treatment benefit.

Study authors concluded that each key severe oral mucositis end point contributes meaningfully to the overall clinical benefit of avasopasem.

References

1. Anderson C, Salvaggio S, De Backer M, Kennedy EP, Buyse M. Net treatment benefit of avasopasem manganese for severe oral mucositis from the ROMAN trial. Presented at. 2023 European Congress on Head and Neck Oncology; March 8-11, 2023; Lisbon, Portugal. Abstract 93.
2. Galera announces presentation of supplemental analysis of phase 3 ROMAN trial at European Congress on Head and Neck Oncology. News release. Galera Therapeutics. March 10, 2023. Accessed March 16, 2023. https://investors.galeratx.com/news-releases/
3. Galera announces FDA acceptance and priority review of avasopasem NDA for radiotherapy-induced severe oral mucositis. News release. Galera Therapeutics. February 15, 2023. Accessed March 16, 2023. https://investors.galeratx.com/news-releases/news-release-details/