Growing Evidence for the Benefit of Targeting Molecular Alterations in Rare Head and Neck Cancer

Data from the phase II open-label ACCURACY trial reported that AL101, a selective inhibitor of gamma secretase, showed activity in patients with adenoid cystic carcinoma (ACC) with evidence of disease progression (Abstract 919MO).

There are currently no approved standard treatments available for patients with recurrent or metastatic ACC. NOTCH mutations have been identified in this disease and are correlated with poor prognosis. AL101, a gamma secretase inhibitor, prevents cleavage of NOTCH at the cell surface, a key role in the activation of the NOTCH signalling pathway. “Because of the slow growth pattern for this tumour, patients are generally followed without any treatment until disease progression and appearance of symptoms. At this point in the disease trajectory, there is limited evidence for systemic treatment regimens,” says Dr Sandra Schmitz from the Institut Roi Albert II Cancer Center, Cliniques Universitaires Saint-Luc (UCLouvain), Brussels, Belgium. In the ACCURACY trial, AL101 led to partial responses (PRs) in 6 out of 40 evaluable patients with recurrent or metastatic ACC harbouring known NOTCH mutations (Notch1-4mut). Most PRs were apparent by week 16, and 21 patients had stable disease (SD). AL101 appeared to be well tolerated. These results are encouraging as several previous early clinical trials investigating other genetic alterations have reported SD as best outcome, and sometimes issues with toxicity.

In terms of future research, Schmitz suggests that identifying the mutational and molecular status of the patients who have primary or recurrent and metastatic disease would be useful to detect other potential targets and understand tumour behaviour.” The ACCURACY study did select patients for NOTCH mutations but other genetic and molecular alterations in ACC have been described too,” she says. “It would therefore be interesting and informative to molecularly profile patients according to response, i.e. those achieving a PR, SD or progressive disease. Several actionable mutations in other genes with a role in processes, such as chromatin regulation and DNA-damage/checkpoint signalling, are known and future research in patients with ACC may be aided by biomarker-driven studies.”

Indeed, a second trial discussed at the ESMO Congress highlights the key role of molecular and genomic sequencing modalities in a wide spectrum of histologic entities of salivary gland carcinoma.

A retrospective analysis of data from 107 patients with metastatic salivary gland tumours treated in early phase clinical trials, showed that there was a trend for greater objective response rates (ORRs) in patients with treatment-matched molecular targets that had higher compared with lower evidence levels of clinical actionability, according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) (Abstract 918MO). Thus, the odds ratio for ORR was 9.8 (p=0.058) for therapies matched to level 1/2 alterations (those ready for implementation in routine clinical decisions, or those likely to define a patient population who would benefit but for whom additional data are needed, respectively) compared with therapies matched to level 3/4 alterations (those with clinical benefit previously demonstrated in other tumour types or for similar molecular targets, and those with preclinical evidence of actionability, respectively). However, median progression-free survival was not different across ESCAT levels (3.4 months versus 12.4 months; hazard ratio 0.6; p=0.23), suggesting that long-term disease control can also be achieved with emerging actionability markers. “Molecular and genomic sequencing modalities should be prioritised over non-molecular guided approaches in patients with metastatic salivary gland carcinoma,” concludes Schmitz. “These data also underline the importance of the ESCAT classification, and highlight that a treatment with demonstrated activity in a given biomarker-driven disease could prove beneficial for patients with these rare head and neck cancers, which could pave the way for molecular-based precision medicine.” Future clinical data are awaited to validate these findings.

Abstract and session details

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