The Phase III BURAN trial, presented at the recent ESMO Congress, evaluated the PI3K inhibitor buparlisib plus paclitaxel in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) who had progressed after PD-1/PD-L1 inhibitor therapy. The study failed to demonstrate improvements in progression-free survival (PFS) or overall survival (OS) compared with paclitaxel alone (median PFS: 4.1 months in both arms; median OS: 9.6 vs 9.7 months), despite a higher objective response rate (ORR) with the combination (30.3% vs 20.7%).While negative, these results underscore a critical unmet need: the absence of a preferred standard therapy after immunotherapy failure in R/M HNSCC. At the same time, comparisons with historical data suggest that outcomes in the immunotherapy era have improved overall. Oncology Frontier invited Denis Soulieres (Centre hospitalier de l’Université de Montréal) to provide an in-depth interpretation of the BURAN study and to discuss future therapeutic directions.
Q1: How Do You Interpret the BURAN Trial Results and Their Clinical Value?
Professor Denis Soulieres: The Phase III BURAN trial was designed based on the earlier Phase II BERIL-1 study, which evaluated buparlisib plus paclitaxel versus paclitaxel alone in patients with R/M HNSCC who had progressed after platinum-based chemotherapy. In BERIL-1, the combination demonstrated not only a higher response rate but also significant improvements in both PFS and OS.
However, BURAN addressed a new and clinically more relevant population—patients who had progressed after PD-1 inhibitor therapy, now widely used as first- or second-line treatment. While the higher response rate observed in BERIL-1 was reproduced in BURAN (ORR 30.3% vs 20.7%), this did not translate into survival benefits. Neither PFS (median 4.1 months in both arms; HR 0.97) nor OS (9.6 vs 9.7 months; HR 1.02) differed between treatment groups.
Therefore, in patients with immunotherapy-refractory disease, buparlisib plus paclitaxel cannot be considered superior to paclitaxel alone. From a clinical standpoint, this confirms that response rate alone is insufficient as a surrogate for survival benefit in this setting.
Q2: What Do These Findings Tell Us About Future Drug Development and Combination Strategies?
Professor Denis Soulieres: The BURAN trial highlights a fundamental challenge: after failure of first-line immunotherapy, we still lack a clearly preferred treatment option. This is perhaps the most important takeaway from the study.
At the same time, BURAN also delivers a more optimistic message. When we compare these results with historical data, such as BERIL-1—where the median OS was only 6.5 months—patients in BURAN achieved median survival exceeding 10 months. This suggests that the overall prognosis of patients treated in the immunotherapy era has improved, even after progression.
Nevertheless, more than 80% of patients eventually progress on frontline immunotherapy, leaving substantial room for improvement. Ongoing research is therefore focusing on novel agents and rational combinations, particularly those integrated with immunotherapy. For example, functional anti-EGFR antibodies combined with pembrolizumab have shown promising response rates in early studies. Whether these responses can be translated into meaningful OS benefit remains to be demonstrated, and randomized trials are currently underway.
Q3: Which Biomarkers Are Most Important for Individualizing Treatment in R/M HNSCC?
Professor Denis Soulieres: At present, PD-L1 expression remains the only biomarker routinely used in clinical practice. Patients with PD-L1–negative tumors (commonly CPS <1), who represent fewer than 10% of cases, derive little benefit from immunotherapy and are generally not candidates for this approach.
However, for the remaining 80% or more of patients, PD-L1 alone is insufficient to guide optimal treatment selection. Although HPV-positive disease—often inferred from p16 overexpression in oropharyngeal cancer—is associated with a better prognosis, its predictive value for response to specific therapies, particularly immunotherapy, remains unclear.
Thus, beyond PD-L1, we currently lack robust biomarkers to inform personalized treatment decisions in R/M HNSCC. The development of novel predictive biomarkers, extending beyond PD-L1, represents one of the most pressing unmet needs in this field.
Conclusion
The BURAN trial, despite its negative primary outcome, provides critical insights into the evolving landscape of R/M HNSCC. It underscores both the progress achieved in the immunotherapy era and the persistent therapeutic gap following immunotherapy failure. Moving forward, advances will depend on biomarker-driven strategies and innovative drug combinations capable of delivering durable survival benefits to this challenging patient population.
Professor Denis Soulieres
